JP2014503571A - Novel 5-alkynyl-pyridine - Google Patents

Abstract

The present invention is characterized by 5-alkynyl-pyridines of general formula (I), their use as inhibitors of PI3Kα activity, pharmaceutical compositions containing them, and excessive or abnormal cell proliferation such as cancer. It relates to their use as medicaments for treating and / or preventing diseases and associated conditions. The groups R ^{1 to} R ⁶ and n have the meaning given in the claims and the specification.

Description

(I)
の５−アルキニル−ピリジン（式中、基Ｒ¹〜Ｒ⁶およびｎは、請求項および明細書中で付与される意味を有する）に関する。本発明の化合物は、過度または異常な細胞増殖によって特徴付けられる疾患の治療に、このような化合物を含む医薬製剤に、および薬剤として使用するのに適している。本発明の化合物は、ＰＩ３Ｋα活性に対して阻害効果を示す。 The present invention is directed to general formula (I):

(I)
5-alkynyl-pyridine in which the groups R ^{1 to} R ⁶ and n have the meanings given in the claims and the description. The compounds of the invention are suitable for use in the treatment of diseases characterized by excessive or abnormal cell proliferation, in pharmaceutical formulations containing such compounds and as medicaments. The compounds of the present invention show an inhibitory effect on PI3Kα activity.

Cell proliferation is the increase in cell number as a result of cell growth and division. In general, cells do not proliferate unless they receive a signal that instructs them to proliferate. When a signal is received, a complex signaling network is activated within the cell.
The phosphoinositide 3-kinase pathway is one of the important pathways activated during cell growth. Phosphoinositide 3-kinase (PI3-kinase or PI3K) phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3′OH-position to produce phosphatidylinositol (3,4,5) -triphosphate (PI). (3,4,5) P3 or PIP3) is generated. The tumor suppressor phosphatase tensin homolog (PTEN) deleted on chromosome 10 dephosphorylates PIP3 to PIP2, thereby terminating PI3K-dependent signaling. PIP3 propagates intracellular signaling that leads to cell proliferation.

In particular, the PI3K pathway is involved in various physiological and pathological functions that affect various human diseases such as cancer, metabolic, inflammatory and cardiovascular diseases. (Wymann MP, Nat Rev Mol Cell Biol. 2008 Feb; 9 (2): 162-76 .; Wymann MP, Curr Opin Cell Biol. 2005 Apr; 17 (2): 141-9).
Of the three classes of PI3K classified by structure and function, class IA PI3K is the most involved in human cancer. It consists of three isoforms, named PI3Kα, β and δ, the role of PI3Kα as a major signaling molecule downstream of receptor tyrosine kinase (RTK) and its involvement in tumorigenesis, growth control and cell survival Has been proven. Indeed, activation of signaling pathways by mutation or amplification of PI3Kα or mutation / deletion of the phosphatase PTEN (the most important negative regulator of the pathway) is found in a large proportion in cancers of various origins. (I. Vivanco & CL Sawyers, Nature Reviews 2002, 2: 489-501).
Inhibition of PI3K signaling can reduce cell proliferation and promote cell death in some situations. As a result, components of this pathway provide an attractive target for cancer therapy, and inhibitors that also target this pathway are important candidates for cancer treatment.
Examples of PI3K inhibitors are disclosed in WO 2006/044823, 2006/040279 and 2009/112565. Nevertheless, there is a need to provide compounds that act as inhibitors of the PI3K pathway.

  Thus, the technical problem underlying the present invention is to provide inhibitors useful for preventing and / or treating diseases characterized by excessive or abnormal cell proliferation such as cancer.

(I)
（式中、基Ｒ¹〜Ｒ⁶およびｎは、明細書および請求項中で定義される通りである）に記載の化合物を提供する。式（Ｉ）に記載の化合物は、細胞の増殖を制御することに関与する特定のシグナル酵素を阻害する。したがって、本発明の化合物は、例えば、これらのシグナル酵素の活性と関連し、かつ過度または異常な細胞増殖によって特徴付けられる疾患を治療するために使用することができる。好ましくは、本発明の化合物は、がんの治療で使用することができる。
より詳細には、本発明の化合物は、ＰＩ３Ｋ経路の強力な阻害効果、および腫瘍細胞に対する、とりわけＰＩ３Ｋを阻害することを通して仲介されるものに対する高い有効性によって特徴付けられる。 The present invention addresses this need, and thus, as a solution to the technical problem, Formula (I):

(I)
Wherein the groups R ^{1 to} R ⁶ and n are as defined in the description and claims. The compounds described in formula (I) inhibit certain signal enzymes involved in controlling cell growth. Thus, the compounds of the present invention can be used, for example, to treat diseases associated with the activity of these signal enzymes and characterized by excessive or abnormal cell proliferation. Preferably, the compounds of the invention can be used in the treatment of cancer.
More particularly, the compounds of the present invention are characterized by a potent inhibitory effect of the PI3K pathway and high efficacy against tumor cells, especially those mediated through inhibiting PI3K.

(I)
の化合物またはその塩に関し、ここで、
Ｒ¹は、−Ｈまたは−ＮＨ₂であり；
Ｒ²は、−Ｎ（Ｒ⁷，Ｒ⁸）であり；
Ｒ³は、−Ｃ_1-5アルキルであり；
Ｒ⁴は、−Ｈ、ハロゲン、−ＣＮ、−Ｃ_1-5アルキル、−Ｏ−Ｃ_1-5アルキル、−Ｃ_1-5アルキル−Ｏ−Ｃ_1-5アルキルまたは−Ｏ−Ｃ_1-5ハロアルキルから選択され； The present invention is therefore of the general formula (I):

(I)
Or a salt thereof, wherein:
R ¹ is —H or —NH ₂ ;
R ² is —N (R ⁷ , R ⁸ );
R ³ is —C _1-5 alkyl;
R ⁴ is —H, halogen, —CN, —C _1-5 alkyl, —O—C _1-5 alkyl, —C _1-5 alkyl-O—C _1-5 alkyl or —O—C _1-5. Selected from haloalkyl;

R ⁵ is —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently 1 One or more ═O, —CN, ═S, halogen, R ¹⁵ or R ¹⁶ optionally substituted); or R ⁵ is —C _6-10 aryl or 5 to 12 membered Heteroaryl (all of these groups are independently selected from one or more —CN, halogen, R ¹⁵ or R ¹⁶ ); or R ⁵ is —N ( R ¹² , R ¹³ );

R ⁶ is halogen, —CN, —C _1-5 alkyl, —C _1-5 haloalkyl, —O—C _1-5 alkyl, —C _1-5 alkyl-O—C _1-5 alkyl or —O—. Selected from C _1-5 -haloalkyl;
n is 0, 1 or 2;
R ⁷ is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O —R ⁹ , —C _1-5 alkyl-S—R ⁹ , or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (all of these groups independently represent one or more ═O , -CN, = S, halogen, or optionally substituted with R ¹¹ );
R ⁸ is —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl. , 3-14 membered heterocyclyl, —C _1-5 alkyl-O—R ⁹ , —C _1-5 alkyl-S—R ⁹ , or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (these All of the groups are independently selected from one or more of ═O, —CN, ═S, halogen, or R ¹¹ ), or

R ⁷ and R ⁸ are the same or different and are —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently one or more —CN, halogen, or R ¹¹ ; R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, are combined with a partially saturated or fully saturated 3-14 membered heterocyclyl (which is optionally substituted) The groups independently form one or more ═O, —CN, ═S, halogen, or R ¹¹ , which may be independently substituted);
R ⁹ is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O —C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups) Are independently selected from one or more ═O, —CN, ═S, halogen, or R ¹¹ );

R ¹⁰ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl. , —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _{1- 5} alkyl) (all of these groups are independently selected from one or more of ═O, —CN, ═S, halogen, or R ¹¹ ); or R ⁹ , R ¹⁰ are the same or different and are —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently substituted with one or more —CN, halogen, or R ^11. Or R ⁹ and R ¹⁰ together with the atoms to which they are attached are 3 Forming a -14 membered heterocyclyl, which group may be independently substituted with one or more ═O, —CN, ═S, halogen, or R ¹¹ ;
R ¹¹ is selected from —OH, —NH ₂ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , —OCF ₃ , —OCHF ₂ , or —nitro; or

R ¹¹ is —C _6-10 aryl or 5-12 membered heteroaryl (all of these groups are independently one or more of —CN, halogen, —OH, —NH ₂ , —CH ₃ , — _{CH 2 CH 3, -CF 3,} -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - Cyclobutyl, -cyclopentyl, -cyclohexyl, -NH-CH ₃ , -N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -N (CH ₃ , CH ₂ CH ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH ₃ ) ₂ , —C (O) NH—CH _{2 CH 3, -C (O)} N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl (Methylpiperazinly), - pyrrolidinyl, - morpholinyl, or - is selected from may also be) optionally substituted with nitro; or R ¹¹ is , —NH—C _1-5 alkyl, —N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl , -C _2-5 alkenyl, -C _2-5 alkynyl, -C _3-10 cycloalkyl, 3-14 membered heterocyclyl (these groups are independently one or more ═O, —CN, ═S , _{halogen, -OH, -NH 2, -CH 3} , -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl , -Butyl, iso-butyl-, t rt- butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH ₃ , CH ₂ CH ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH ₃ ) ₂ , —C _{(O) NH-CH 2 CH} 3, -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl, - Selected from N-methylpiperazinyl, -pyrrolidinyl, -morpholinyl, or -nitro);

R ¹² is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O —C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups) Are independently selected from one or more ═O, —CN, ═S, halogen, or R ¹⁴ );
R ¹³ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl. , —C _6-10 aryl, 5-12 membered heteroaryl, —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _{1— 5} alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups are independently substituted with one or more ═O, —CN, ═S, halogen, or R ^14. Or may be selected from; or

R ¹² , R ¹³ are the same or different and are —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently one or more —CN, halogen, or R ¹⁴ ; or are independently selected from optionally substituted); or R ¹² and R ^13, together with the nitrogen atom to which they are attached, 3-14 membered heterocyclyl (the group may independently One or more ═O, —CN, ═S, halogen, or R ¹⁴ );
R ¹⁴ is selected from —OH, —NH ₂ , —CF ₃ , —OCF ₃ , —OCHF ₂ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , or —nitro; or R ¹⁴ is —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently one or more —CN, halogen, —OH, —NH ₂ , —CH ₃ , — _{CH 2 CH 3, -CF 3,} -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - Cyclobutyl, -cyclopentyl, -cyclohexyl, -NH-CH ₃ , -N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -N (CH ₃ , CH ₂ CH _{3 ), - O-CH 3,} -O-CH 2 CH 3, -S-CH 3, -C (O) NHC _{3, -C (O) N (} CH 3) 2, -C (O) NH-CH 2 CH 3, -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl, or - is selected from nitro may be substituted by); or

R ¹⁴ represents —NH—C _1-5 alkyl, —N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _{1. -5} alkyl, -C _2-5 alkenyl, -C _2-5 alkynyl, -C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently one or more = 0, -CN, = S, _{halogen, -H, -OH, -NH 2,} -CH 3, -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 _{CH 3) 2, -NH-CH} 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH ₃ ) ₂ , —C (O) NH—CH ₂ CH ₃ , —C (O) N (CH _{2 CH 3) 2, -C (} O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl or - nitro May be selected);
R ¹⁵ and R ¹⁶ are the same or different and are independently —OH, —NH ₂ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , —OCF ₃ , —OCHF _2. Or selected from -nitro; or

R ¹⁵ and R ¹⁶ are the same or different and independently represent —NH—C _1-5 alkyl, —N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, — S—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are Independently, one or more of ═O, —CN, ═S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH ₃ , — C (O) CH _3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3 ) ₂ , —N (CH ₂ CH ₃ ) ₂ , —NH—CH ₂ CH ₃ , —N (CH ₃ , CH ₂ C H ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH ₃ ) ₂ , —C (O) NH _{-CH 2 CH 3, -C (O} ) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-Mechirupipe Or (optionally substituted with razinyl, -pyrrolidinyl, -morpholinyl, or -nitro); or

R ¹⁵ and R ¹⁶ may be the same or different and independently represent —C _6-10 aryl or 5-12 membered heteroaryl (all of these groups are independently one or more —CN, halogen, — _{OH, -NH 2, -CH 3,} -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3 , —N (CH ₃ , CH ₂ CH ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH _{3 ) 2, -C (O) NH} -CH 2 CH 3, -C (O) N (CH 2 CH 3) 2, - (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl or - nitro may be substituted by) Or R ¹⁵ and R ¹⁶ , together with the atoms to which they are attached, are either partially saturated or fully saturated —C _3-10 cycloalkyl or 4-8 membered heterocyclyl (all of these groups Are independently one or more of ═O, —CN, ═S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH _{3. , -C (O) CH 3,} - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - cyclohexyl, - _{NH-CH 3, -N (CH} 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, - _{O-CH 2 CH 3, -S} -CH 3, -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O) NHCH 2 CH 3, -C (O) _{N (CH 2 CH 3) 2} , -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl or - Optionally substituted with nitro).

In one aspect, the invention relates to compounds of formula (I), wherein R ¹ is —H.
In another aspect, the invention relates to compounds of formula (I), wherein R ¹ is —NH ₂ .
In another embodiment, the present invention provides compounds of formula (I) wherein R ³ is —C _1-5 alkyl, preferably —C _1-3 alkyl, more preferably —CH ₃ or —CH ₂ CH ₃ . A compound).
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁴ is —H, halogen, —CN, —C _1-5 alkyl, —O—C _1-5 alkyl, —C _1-5 Alkyl-O—C _1-5 alkyl, or —O—C _1-5 haloalkyl). Preferably R ⁴ is —H, —C _1-5 alkyl or —O—C _1-5 alkyl. The most preferred substituent is —H, —CH ₃ or —O—CH ₃ .
In another aspect, the present invention relates to a compound of formula (I) wherein n is 0.

In another embodiment, the present invention provides compounds of formula (I) wherein R ⁶ is halogen, —CN, —C _1-5 alkyl, —C _1-5 haloalkyl, —O—C _1-5 alkyl, — C _1-5 alkyl-O—C _1-5 alkyl, or —O—C _1-5 haloalkyl). Preferably R ⁶ is —C _1-5 alkyl.
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁵ is —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, or —N (R ¹² , R ¹³ ) (all of these groups are independently substituted with one or more ═O, —CN, ═S, halogen, R ¹⁵ or R ¹⁶ . And R ¹⁵ and R ¹⁶ are defined as described in the specification and claims).

In another embodiment, the present invention provides compounds of formula (I) wherein R ⁵ is —C _6-10 aryl or 5-12 membered heteroaryl (all of these groups are independently one or more -CN, halogen, optionally substituted with R ¹⁵ or R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are selected as defined in the description and claims).
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁵ is —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently Optionally substituted with one or more ═O, —CN, ═S, halogen, R ¹⁵ or R ¹⁶ , where R ¹⁵ and R ¹⁶ are defined as described in the specification and claims. )].
In one embodiment, the present invention provides compounds of formula (I) wherein R ⁵ is —C _1-5 alkyl, preferably —C _1-3 alkyl, more preferably —CH ₃ (all of these groups are Independently, it may be substituted with one or more ═O, —CN, ═S, halogen, R ¹⁵ or R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are defined as described in the specification and claims. The compound selected from In a more preferred embodiment, R ⁵ is —C _1-5 alkyl substituted with one or more —O—C _1-3 alkyl, preferably —O—CH ₃ .

In one aspect, the invention provides a compound of formula (I) wherein R ⁵ is selected from —C _3-10 cycloalkyl, preferably R ⁵ is —C _3-6 cycloalkyl, more preferably cyclo Propyl, or cyclohexyl (all of these groups may be independently substituted with one or more ═O, —CN, ═S, halogen, R ¹⁵ or R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are As defined in the specification and claims).
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁵ is —C _6-10 aryl, more preferably R ⁵ is phenyl, both of which are independently 1 One or more —CN, halogen, R ¹⁵ or R ¹⁶ , where R ¹⁵ and R ¹⁶ are as defined in the specification and claims. In a further preferred embodiment, R ⁵ is phenyl substituted with one or more halogens, more preferably one or more —F.
In another preferred embodiment, R ⁵ is phenyl substituted with one or more R ¹⁵ or R ¹⁶ , wherein R ¹⁵ or R ¹⁶ is —O—C _1-5 alkyl, preferably it is -O-CH _3.
In one aspect, the invention provides a compound of formula (I) wherein R ⁵ is a 5-12 membered heteroaryl, preferably R ⁵ is pyridinyl, imidazolyl, pyrazolyl, thiophenyl, furyl, N-methyl- Pyrazolyl, N-methyl-imidazolyl (all of these groups may independently be substituted with one or more —CN, halogen, R ¹⁵ or R ¹⁶ , R ¹⁵ and R ¹⁶ may be And as defined in the claims).

When R ⁵ is a 5-12 membered heteroaryl, the compound exhibits improved solubility.
In preferred embodiments, R ⁵ is a 5-12 membered heteroaryl substituted with one or more —C _1-3 alkyl, preferably —CH ₃ , or substituted with halogen, preferably —Cl. ing.
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁵ is —N (R ¹² , R ¹³ ), and R ¹² and R ¹³ are as defined in the description and claims. ).

In preferred embodiments, R ¹² and R ¹³ are taken together with the nitrogen atom to which they are attached to a 3 to 14 membered heterocyclyl (the group is independently one or more ═O, —CN, ═S, halogen, or R ¹⁴ , where R ¹⁴ is defined as described in the specification and claims.
In preferred embodiments, R ⁵ is pyrrolidinyl and the group may independently be substituted with one or more ═O, —CN, ═S, halogen, or R ¹⁴ , where R ¹⁴ is As defined in the description and claims.
In one embodiment, the present invention provides compounds of formula (I) wherein R ⁷ is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cyclo Alkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—R ⁹ , —C _1-5 alkyl-S—R ⁹ , or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (these All of the groups may independently be substituted with one or more ═O, —CN, ═S, halogen, or R ¹¹ , and R ⁹ , R ^10, and R ¹¹ may be Selected from those defined in the section above].

In preferred embodiments, the present invention provides compounds of formula (I) wherein R ⁷ is —H, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, or —C _{1— 5} alkyl-N (R ⁹ , R ¹⁰ ) (all of these groups may independently be substituted with one or more ═O, —CN, ═S, halogen, or R ¹¹ ; ⁹ , R ¹⁰ and R ¹¹ are selected from) as defined in the description and claims.
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁷ , R ⁸ are the same or different and independently represent —C _6-10 aryl, 5-12 membered heteroaryl (of these groups All are independently selected from one or more —CN, halogen, or R ¹¹ , where R ¹¹ is defined as defined in the specification and claims) Relates to compounds.
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁸ is —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _{2— 5} alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—R ⁹ , —C _1-5 alkyl-S—R ⁹ , or — C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (all of these groups may independently be substituted with one or more ═O, —CN, ═S, halogen, or R ^11. Often, R ⁹ , R ¹⁰ and R ¹¹ are selected from) as defined in the description and claims.

In preferred embodiments, the present invention provides compounds of formula (I) wherein R ⁸ is —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _{3 — 10} cycloalkyl, 3-14 membered heterocyclyl, or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (all of these groups are independently one or more of ═O, —CN, ═S , Halogen, or R ¹¹ , wherein R ⁹ , R ¹⁰ and R ¹¹ are selected as defined in the description and claims).
In another embodiment, the present invention provides compounds of formula (I) wherein R ² is —N (R ⁷ , R ⁸ ), wherein R ⁷ and R ⁸ are defined as described in the specification and claims. And R ⁷ and R ⁸ together with the nitrogen atom to which they are attached may be substituted with one or more ═O, —CN, ═S, halogen, or R ^11. Forming a partially saturated or fully saturated 3-14 membered heterocyclyl, wherein R ¹¹ is defined as described in the specification and claims).
In preferred embodiments, R ² is independently one or more ═O, —CN, ═S, halogen, or morpholinyl optionally substituted with R ¹¹ , wherein R ¹¹ is As defined in the description and claims. In a preferred embodiment, R ¹¹ is —C _1-3 alkyl, preferably —CH ₃ .

In another preferred embodiment, R ² is independently piperazinyl optionally substituted with one or more ═O or R ¹¹ . In preferred embodiments, R ¹¹ is selected from —CH ₃ , —cyclopropyl, —C (O) CH ₃ , —S (O) ₂ CH ₃ .
In further preferred embodiments, R ² is independently substituted with one or more ═O, —CN, ═S, halogen, or R ¹¹ , and in preferred embodiments —C (O) CH. [1,4] diazepanyl substituted with ₃ .
In further preferred embodiments, R ² is independently substituted with one or more ═O, —CN, ═S, halogen, or R ^{11. In} preferred embodiments, independently, one Or piperidine substituted with a plurality of ═O, —CH ₃ , —OH, —S (O) ₂ CH ₃ , —O—CH ₃ .
In another aspect, the invention relates to compounds of formula (I) wherein R ⁷ is —C _1-3 alkyl or tetrahydropyranyl.
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁹ is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 Cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups may independently be substituted with one or more ═O, —CN, ═S, halogen, or R ¹¹ , ¹¹ is selected from) as defined in the description and claims.

In another embodiment, the present invention provides compounds of formula (I) wherein R ⁹ is —H, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 Alkyl-O—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-3 alkyl, C _1-3 alkyl) (all of these groups independently represent one or more ═O , —CN, ═S, halogen, or R ¹¹ , wherein R ¹¹ is selected as defined in the specification and claims).
In another embodiment, the present invention provides compounds of formula (I) wherein R ⁹ , R ¹⁰ are the same or different and are independently -C _6-10 aryl, 5-12 membered heteroaryl (of these groups All are independently selected from one or more —CN, halogen, or R ¹¹ , where R ¹¹ is defined as defined in the specification and claims) Relates to compounds.
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁰ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _{2. -5} alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or — C _1-5 alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups are independently one or more of ═O, —CN, ═S, halogen, or R ^11. And R ¹¹ is selected from as defined in the specification and claims).

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁰ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _3-10 cycloalkyl, 14-membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-3 alkyl, C _1-3 alkyl) (all of these groups are independently And may be substituted with one or more ═O, —CN, ═S, halogen, or R ¹¹ , where R ¹¹ is defined as described in the specification and claims. ] About the compound of this.
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹¹ is —OH, —NH ₂ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , — OCF ₃ , —OCHF ₂ , —CN, or —nitro, —NH—C _1-5 alkyl, —N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, —S —C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently One or more of ═O, —CN, ═S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH _3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl , - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O _{-CH 3, -O-CH 2 CH} 3, -S-CH 3, -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O) NHCH 2 CH 3, _{-C (O) N (CH 2} CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, -Morpholinyl, or optionally substituted with -nitro).

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹¹ is —C _6-10 aryl or 5-12 membered heteroaryl, wherein all of these groups are independently one or more -CN, _{halogen, -OH, -NH 2, -CH 3} , -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, - _{NHCH 2 CH 3, -N (CH} 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, -S-CH 3, -C (O) NHCH 3, -C ( O) N (CH ₃ ) ₂ , —C (O) NH—CH ₂ CH ₃ , —C (O) N (CH ₂ CH ₃ ) ₂ , -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl, or - may be substituted with nitro ) Selected from the above.

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹¹ is —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH _{3 , -C (O) CH 3,} - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - cyclohexyl, -NH-CH _3, -N ( _{CH 3) 2, -N (CH} 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, - _{S-CH 3, -C (O} ) NHCH 3, -C (O) N (CH 3) 2, -C (O) N (CH 2 CH 3) 2, -C (O) NHCH 2 CH 3 , -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-menu Rupiperajiniru, - pyrrolidinyl, - morpholinyl, halogen, -CN, or - a compound of selected from nitro) relates.

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹² is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 Cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (— C _1-5 alkyl, —C _1-5 alkyl) (all of these groups may be independently substituted with one or more ═O, —CN, ═S, halogen, or R ^14. , R ¹⁴ is defined as defined in the specification and claims).
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹² is —H, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 Alkyl-O—C _1-5 alkyl, or —C _1-5 alkyl-N (—C _1-3 alkyl, —C _1-3 alkyl) (all of these groups independently represent one or more ═O, —CN, ═S, halogen, or R ¹⁴ , wherein R ¹⁴ is selected as defined in the description and claims.
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹² and R ¹³ are the same or different and independently represent —C _6-10 aryl, 5-12 membered heteroaryl (of these groups All are independently selected from one or more —CN, halogen, or R ¹⁴ , where R ¹⁴ is defined as defined in the specification and claims) Relates to compounds.

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹³ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _{2. -5} alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or — C _1-5 alkyl-N (—C _1-5 alkyl, —C _1-5 alkyl) (all of these groups are independently one or more of ═O, —CN, ═S, halogen, or R ¹⁴ optionally substituted with R ¹⁴ , wherein R ¹⁴ is defined as defined in the description and claims).
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹³ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _3-10 cycloalkyl, 14-membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, or —C _1-5 alkyl-N (—C _1-3 alkyl, —C _1-3 alkyl) (all of these groups are Independently selected from one or more ═O, —CN, ═S, halogen, or R ¹⁴ , where R ¹⁴ is defined as described in the specification and claims. It is related with the compound of.
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹² and R ¹³ together with the atoms to which they are attached are independently one or more ═O, —CN , = S, halogen, or R ¹⁴ , optionally substituted with 3-14 membered heterocyclyl, wherein R ¹⁴ is defined as described in the specification and claims.

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁴ is —OH, —NH ₂ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , — OCF ₃ , —OCHF ₂ , or —nitro, —NH—C _1-5 alkyl, —N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _{1 -5} alkyl, -C _1-5 alkyl, -C _2-5 alkenyl, -C _2-5 alkynyl, -C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently 1 One or more of ═O, —CN, ═S, halogen, —H, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH _3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O- _{CH 3, -O-CH 2 CH} 3, -S-CH 3, -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O) NHCH 2 CH 3, - _{C (O) N (CH 2} CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - Selected from morpholinyl, or optionally substituted with -nitro).

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁴ is —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently one or more -CN, _{halogen, -OH, -NH 2, -CH 3} , -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, - _{NHCH 2 CH 3, -N (CH} 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, -S-CH 3, -C (O) NHCH 3, -C ( _{O) N (CH 3) 2} , -C (O) NH-CH 2 CH 3, -C (O) N (CH 2 CH 3) 2, C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl, or - nitro may be substituted by) Selected].
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁴ is —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH _{3. , -C (O) CH 3,} - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH _{3) 2, -N (CH 2} CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, -S _{-CH 3, -C (O) NHCH} 3, -C (O) N (CH 3) 2, -C (O) N (CH 2 CH 3) 2, -C (O) NHCH 2 CH 3, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylcarbamoyl Lpiperazinyl, -pyrrolidinyl, -morpholinyl, halogen, -CN, or -nitro).

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁵ and R ¹⁶ are the same or different and are independently —OH, —NH ₂ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , —OCF ₃ , —OCHF ₂ , —CN, or —nitro, —NH—C _1-5 alkyl, —N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 Membered heterocyclyl (all of these groups are independently one or more of ═O, —CN, ═S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , _{-S (O) 2 CH 3,} -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert butyl Le -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, _{CH 2 CH 3), - O} -CH 3, -O-CH 2 CH 3, -S-CH 3, -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O _{) NH-CH 2 CH 3,} -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N- Selected from methylpiperazinyl, -pyrrolidinyl, -morpholinyl, or -nitro).

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁵ and R ¹⁶ are the same or different and are independently -C _6-10 aryl or 5-12 membered heteroaryl (of these groups All are independently one or more of —CN, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O ) CH _3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, _{-N (CH 2 CH 3) 2} , -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, -S-CH 3, _{-C (O) NHCH 3, -C} (O) N (CH 3) 2, -C (O) NHCH 2 _{CH 3, -C (O) N} (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, -Optionally substituted with pyrrolidinyl, -morpholinyl, or -nitro).

In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁵ and R ¹⁶ are the same or different and are independently —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , — _{CF 3, -F, -Cl, -Br} , -CN, - _{nitro, -NH-CH 3, -N (} CH 3) 2, -NH (CH 2 CH 3), - N (CH 2 CH 3) 2 , —N (CH ₃ , CH ₂ CH ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) -pyrazolidinyl, —OCF ₃ , —OCHF _2. ).
In another embodiment, the present invention provides compounds of formula (I) wherein R ¹⁵ and R ¹⁶ are taken together with the atoms to which they are attached to 3-14 membered heterocyclyl (independently one or a plurality of = O, -CN, = S, _{halogen, -OH, -NH 2, -CH 3} , -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3 , - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N ( _{CH 2 CH 3) 2, -NH} -CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, -S-CH 3, -C ( _{O) NHCH 3, -C (O} ) N (CH 3) 2, -C (O) N (CH 2 CH 3) 2, -C ( _{) NH-CH 2 CH 3,} -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl or - nitro Which may be substituted with a).

In another aspect, the invention relates to compounds of formula (I), wherein R ¹ is —NH ₂ and R ⁵ is —C _1-5 alkyl.
The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, and prodrugs of the compounds of general formula (I) or any of the compounds in the embodiments as previously disclosed.
In another aspect, the invention relates to a compound of general formula (I) or any compound in embodiments as disclosed above for use in the treatment of cancer.
In another aspect, the invention relates to a compound of general formula (I) or any of the embodiments as disclosed previously, or a pharmaceutically acceptable salt thereof, as a medicament.
In another aspect, the present invention provides a compound of general formula (I) or an embodiment as previously disclosed for use in the treatment and / or prevention of cancer, infectious diseases, inflammation, and autoimmune diseases. Or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to cancer, preferably breast, prostate, brain or ovarian cancer, non-small cell bronchial cancer (NSCLC), melanoma, and chronic lymphocytic leukemia (CLL), or a pathway thereof. A compound of general formula (I) or any of the embodiments as previously disclosed for use in the treatment and / or prevention of cancers of the type activated by a PI3K mutation or PTEN deletion Or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to breast, prostate, brain or ovarian cancer, non-small cell bronchial cancer (NSCLC), melanoma, and chronic lymphocytic leukemia (CLL), or a pathway thereof that is a PI3K mutation or A compound of general formula (I) or any of the embodiments as previously disclosed, or a compound thereof, for use in the treatment and / or prevention of a type of cancer activated by a deletion of PTEN; It relates to a pharmaceutically acceptable salt.
In another aspect, the invention provides a human with a therapeutically effective amount of a compound of general formula (I) or any of the compounds in the embodiments as previously disclosed, or one of its pharmaceutically acceptable salts. To a method for treating and / or preventing cancer.

In another aspect, the present invention provides as an active substance one or more compounds of general formula (I) or any of the compounds in the embodiments as previously disclosed, or pharmaceutically acceptable salts thereof In a pharmaceutical formulation, optionally in combination with conventional excipients and / or carriers.
In another aspect, the invention provides a compound of general formula (1) or any of the compounds in the embodiments as previously disclosed, or one of its pharmaceutically acceptable salts, and formula (1) The invention relates to a pharmaceutical preparation comprising at least one other cytostatic or cytotoxic active substance different from.
Definitions Terms not specifically defined herein have meanings that will be apparent to those skilled in the art in light of all disclosures and the overall context.
As used herein, the following definitions apply unless otherwise indicated:
In the groups, radicals or moieties defined below, the number of carbon atoms is often specified before the group, for example, -C _1-5 alkyl has _1-5 carbon atoms. Means an alkyl group or a radical. In general, in the case of a group comprising two or more subgroups, the first subgroup listed is the radical attachment point, eg, a substituent, —C _1-5 alkyl-C _3-10 cycloalkyl, means a C _3-10 cycloalkyl group attached to a C _1-5 alkyl, the C _1-5 alkyl is bonded to the core structure, or the group to which the substituent is bound.

An indication of the number of members in a group containing one or more heteroatoms (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) is all atoms of all ring or chain members Applies to the number, or the total number of all ring and chain members. One skilled in the art will recognize that substituents containing nitrogen atoms can also be designated as amines or aminos. Similarly, a group containing an oxygen atom may be represented as -oxy, for example alkoxy. A group containing —C (O) — can also be shown as carboxy, a group containing —NC (O) — can be shown as an amide, and a group containing —NC (O) N— as urea And groups containing -NS (O) _2- can also be shown as sulfonamides.
Alkyl means a monovalent saturated hydrocarbon chain, which can exist in both linear and branched forms. If alkyl is substituted, the substitution can occur independently of one another on each carbon atom carrying hydrogen, in each case by mono- or polysubstitution.

The term “C _1-5 alkyl” includes, for example, methyl (Me; —CH ₃ ), ethyl (Et; —CH ₂ CH ₃ ), 1-propyl (n-propyl; n-Pr; —CH ₂ CH ₂ CH _3), 2-propyl (i-Pr; iso- _{propyl; -CH (CH 3) 2)} , 1- butyl (n- _{butyl; n-Bu; -CH 2 CH} 2 CH 2 CH 3), 2- methyl 1-propyl (an _{iso-butyl; i-Bu; -CH 2 CH} (CH 3) 2), 2- butyl (sec-butyl; sec-Bu; -CH (CH 3) CH 2 CH 3), 2- methyl-2-propyl (tert- butyl; t-Bu; -C (CH 3) 3), 1- pentyl (n- _{pentyl; -CH 2 CH 2 CH 2 CH} 2 CH 3), 2- pentyl (-CH _{(CH 3) CH 2 CH 2} CH 3), 3- pentyl _{(-CH (CH 2 CH 3)} 2), 3-methyl-1-butyl (an _{iso-pentyl; -CH 2 CH 2 CH (CH} 3) 2), 2- methyl-2-butyl _{(-C (CH 3) 2 CH} 2 CH 3), 3- methyl - 2-butyl (—CH (CH ₃ ) CH (CH ₃ ) ₂ ), 2,2-dimethyl-1-propyl (neo-pentyl; —CH ₂ C (CH ₃ ) ₃ ), 2-methyl-1-butyl (—CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ).
The terms propyl, butyl, pentyl and the like, without further definition, mean a saturated hydrocarbon group having the corresponding number of carbon atoms and encompass all isomeric forms.

The above definition for alkyl also applies when alkyl is part of another group, for example C _xy alkylamino, C _xy alkyloxy, or C _xy alkoxy, such as C _xy alkyloxy and C _xy Alkoxy points to the same group.
The term “alkylene” can also be derived from alkyl. Alkylene, unlike alkyl, is divalent and requires two binding partners. Formally, the second valence is created by removing a hydrogen atom in the alkyl. Corresponding groups are, for example, —CH ₃ and —CH ₂ , —CH ₂ CH ₃ and —CH ₂ CH ₂ or> CHCH ₃ .
The term “C _1-4 alkylene” includes, for example, — (CH ₂ ) —, — (CH ₂ —CH ₂ ) —, — (CH (CH ₃ )) —, — (CH ₂ —CH ₂ —CH ₂ ). _{-, - (C (CH 3} ) 2) -, - (CH (CH 2 CH 3)) -, - (CH (CH 3) -CH 2) -, - (CH 2 -CH (CH 3)) - , — (CH ₂ —CH ₂ —CH ₂ —CH ₂ ) —, — (CH ₂ —CH ₂ —CH (CH ₃ )) —, — (CH (CH ₃ ) —CH ₂ —CH ₂ ) —, — _{(CH 2 -CH (CH 3)} -CH 2) -, - (CH 2 -C (CH 3) 2) -, - (C (CH 3) 2 -CH 2) -, - (CH (CH 3) _{-CH (CH 3)) -,} - (CH 2 -CH (CH 2 CH 3)) -, - (CH (CH 2 CH 3) -CH 2) -, - (CH (CH 2 CH 2 CH 3) )-,-(CHCH (CH ₃ ) ₂ )-and -C (C _{H 3) (CH 2 CH 3} ) - including.

Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2, 2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene and the like.
The generic terms propylene, butylene, pentylene, hexylene and the like, without further definition, mean all possible isomeric forms with the corresponding number of carbon atoms, ie propylene includes 1-methylethylene, Butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.
The above definition for alkylene also applies when the alkylene is part of another group, for example HO—C _xy alkylene amino or H ₂ N—C _xy alkyleneoxy.
Unlike alkyl, alkenyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked together by a C—C double bond. In an alkyl as defined above having at least two carbon atoms, the two hydrogen atoms on adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, correspondingly Alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl- Prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, penta-1-enyl, penta- 2-enyl, penta-3-enyl, penta-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hexa-1- Enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, hexa-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene 3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, butane 1,3-dienyl, 2,3-dimethylbuta-1,3-diene and the like.
The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, etc., without further definition, mean all possible isomeric forms with the corresponding number of carbon atoms That is, propenyl includes prop-1-enyl and prop-2-enyl, butenyl is but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1 -Enyl, 1-methyl-prop-2-enyl and the like.

The alkenyl can optionally be present in a cis or trans, or E or Z orientation with respect to the double bond.
The above definition for alkenyl also applies when alkenyl is part of another group, for example C _xy alkenylamino or C _xy alkenyloxy.
Unlike alkylene, alkenylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked together by a C—C double bond. In an alkylene as defined above having at least two carbon atoms, if two hydrogen atoms of adjacent carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding alkenylene Is formed.
Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2 , 2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene and the like.

The generic terms propenylene, butenylene, pentenylene, hexenylene, etc. mean all possible isomeric forms with the corresponding number of carbon atoms without further definition, i.e. propenylene includes 1-methylethenylene. Butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.
Alkenylene can optionally be present in a cis or trans, or E or Z orientation with respect to the double bond.
The above definition for alkenylene also applies when the alkenylene is part of another group, for example HO—C _xy alkenylene amino or H ₂ N—C _xy alkenyleneoxy.
Unlike alkyl, alkynyl consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked together by a C—C triple bond. In an alkyl as defined above having at least two carbon atoms, if two hydrogen atoms are formally removed on each adjacent carbon atom and the free valences are saturated to form two additional bonds Alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, penta-1 -Inyl, penta-2-ynyl, penta-3-ynyl, penta-4-ynyl, 3-methyl-but-1-ynyl.
The generic terms propynyl, butynyl, pentynyl and the like, without further definition, mean all possible isomeric forms with the corresponding number of carbon atoms, i.e. propynyl means prop-1-ynyl and prop-2 -Inyl includes butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl.
If the hydrocarbon chain carries both at least one double bond and even at least one triple bond, by definition it belongs to the alkynyl subgroup.
The above definition for alkynyl also applies when alkynyl is part of another group, for example C _xy alkynylamino or C _xy alkynyloxy.

Unlike alkylene, alkynylene consists of at least two carbon atoms, where at least two adjacent carbon atoms are linked together by a C—C triple bond. In an alkylene as defined above having at least two carbon atoms, if two hydrogen atoms of each adjacent carbon atom are formally removed and the free valence is saturated to form two additional bonds Alkynylene is formed.
Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2 -Dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene and the like.
The generic terms propynylene, butynylene, pentynylene, etc., without further definition, mean all possible isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene, butinylene is 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.
The above definition for alkynylene also applies when alkynylene is part of another group, for example HO—C _xy alkynylene amino or H ₂ N—C _xy alkynyleneoxy.

A heteroatom means oxygen, nitrogen and sulfur atoms.
Haloalkyl (haloalkenyl, haloalkynyl) is obtained by substituting one or more hydrogen atoms of a hydrocarbon chain independently of one another from a previously defined alkyl (alkenyl, alkynyl) with a halogen atom, which may be the same or different. Derived. When a haloalkyl (haloalkenyl, haloalkynyl) is further substituted, the substitution can occur, independently of one another, in monosubstituted or polysubstituted forms at each of all carbon atoms carrying hydrogen.
Haloalkyl (haloalkenyl, haloalkynyl) Example _{of, -CF 3, -CHF 2, -CH} 2 F, -CF 2 CF 3, -CHFCF 3, -CH 2 CF 3, -CF 2 CH 3, -CHFCH 3 _{, -CF 2 CF 2 CF 3,} -CF 2 CH 2 CH 3, -CF = CF 2, -CCl = CH 2, -CBr = CH 2, -CI = CH 2, -C≡C-CF 3, - CHFCH ₂ CH ₃ , —CHFCH ₂ CF ₃ and the like.

The term haloalkylene (haloalkenylene, haloalkynylene) is also derived from the previously defined haloalkyl (haloalkenyl, haloalkynyl). Haloalkylene (haloalkenyl, haloalkynyl), unlike haloalkyl, is divalent and requires two binding partners. Formally, the second valence is formed by removing a hydrogen atom from a haloalkyl.
Corresponding groups are, for example, —CH ₂ F and —CHF—, —CHFCH ₂ F and —CHFCHF— or> CFCH ₂ F, and the like.
The above definition also applies when the relevant halogen group is part of another group.
Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.
Cycloalkyl is composed of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings which are subgroups. This system is saturated. In a bicyclic hydrocarbon ring, the two rings are linked together such that the rings share at least two carbon atoms. In a spiro-hydrocarbon ring, one carbon atom (spiro atom) belongs to two rings simultaneously. If a cycloalkyl is substituted, the substitution can occur, independently of one another, in the form of mono- or polysubstitution on each of all carbon atoms carrying hydrogen. Cycloalkyl itself can be linked as a substituent to the molecule via any suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.2.1] octyl, bicyclo [ 2.2.2] octyl, bicyclo [4.3.0] nonyl (octahydroindenyl), bicyclo [4.4.0] decyl (decahydronaphthalene), bicyclo [2.2.1] heptyl (norbornyl) ), Bicyclo [4.1.0] heptyl (norcaranyl), bicyclo- [3.1.1] heptyl (pinanyl), spiro [2.5] octyl, spiro [3.3] heptyl and the like.
The above definition for cycloalkyl also applies when cycloalkyl is part of another group, for example C _xy cycloalkylamino or C _xy cycloalkyloxy.
When the free valence of the cycloalkyl is saturated, an alicyclic group is obtained.
Thus, the term cycloalkylene can be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkyl.

である。 Corresponding groups are for example

It is.

The above definition for cycloalkylene also applies when cycloalkylene is part of another group, for example HO—C _xy cycloalkyleneamino or H ₂ N—C _xy cycloalkyleneoxy.
Cycloalkenyl is also composed of subgroups of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, this system is unsaturated, ie there is at least one C—C double bond but it is not an aromatic system. In cycloalkyl as defined above, when two hydrogen atoms of adjacent ring carbon atoms are formally removed and the free valence is saturated to form a second bond, the corresponding cycloalkenyl is obtained. . When cycloalkenyl is substituted, the substitution can occur, independently of one another, in the form of mono- or polysubstitution on each of all carbon atoms carrying hydrogen. Cycloalkenyl itself can be linked as a substituent to the molecule via any suitable position of the ring system.

  Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexa-enyl 1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta- 1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1, 4-dienyl, cyclohexa-2,5-dieni Bicyclo [2.2.1] hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo [2.2.1] hept-2-enyl (norbornenyl), spiro [4.5] deca -2-ene and the like.

である。
シクロアルケニレンに関する上記の定義は、例えばＨＯ−Ｃ_x-yシクロアルケニレンアミノまたはＨ₂Ｎ−Ｃ_x-yシクロアルケニレンオキシのように、シクロアルケニレンが別の基の一部である場合にも適用される。 The above definition for cycloalkenyl also applies when cycloalkenyl is part of another group, for example C _xy cycloalkenylamino or C _xy cycloalkenyloxy.
When the free valence of cycloalkenyl is saturated, an unsaturated alicyclic group is obtained.
Thus, the term cycloalkenylene can be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example

It is.
The above definition for cycloalkenylene also applies when the cycloalkenylene is part of another group, for example HO—C _xy cycloalkenyleneamino or H ₂ N—C _xy cycloalkenyleneoxy.

Aryl means a monocyclic, bicyclic or tricyclic group having at least one aromatic carbocyclic ring. Preferably, it is a monocyclic group having 6 carbon atoms (phenyl), or a bicyclic group having 9 or 10 carbon atoms (two 6-membered rings, or one 6-membered ring + 5 membered ring Where the second ring may be aromatic but may be saturated or partially saturated. If aryl is substituted, the substitution can occur, independently of one another, in mono- or poly-substituted forms on each of all carbon atoms that carry hydrogen. Aryl itself can be linked to the molecule as a substituent via all suitable positions of the ring system.
Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2- Dihydronaphthyl), fluorenyl and the like.

である。 The above definition for aryl also applies when aryl is part of another group, for example arylamino or aryloxy.
When the aryl free valence is saturated, an aromatic group is obtained.
The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valence is formed by removing a hydrogen atom from an aryl. Corresponding groups are for example

It is.

The above definition for arylene also applies when arylene is part of another group, for example HO-aryleneamino or H ₂ N-aryleneoxy.
Heterocyclyl is derived from the previously defined cycloalkyl, cycloalkenyl and aryl from one or more of the groups —CH ₂ — in the hydrocarbon ring, independently of one another, the groups —O—, —S— or —NH—. Or a ring system derived by replacing one or more of the group ═CH— with the group ═N—, wherein there can be no more than 5 heteroatoms in total. At least one carbon atom may be present between two oxygen atoms, between two sulfur atoms, or between one oxygen and one sulfur atom, the ring being chemically stable as a whole Must have sex. Heteroatoms can optionally be present in all possible oxidation stages (sulfur → sulfoxide-SO, sulfone-SO ₂ —; nitrogen → N-oxide). In heterocyclyl, there is no aromatic ring, ie the heteroatom is not part of an aromatic system.

  As a direct result of being derived from cycloalkyl, cycloalkenyl and aryl, heterocyclyl is a subgroup of monocyclic, bicyclic, tricyclic and spiro-heterocycles (which are saturated) Or can exist in unsaturated form). Unsaturated means that there is at least one double bond in the ring system, but no heteroaromatic system is formed. In a bicyclic heterocycle, the two rings are linked together so that the rings have at least two (hetero) atoms in common. In spiro-heterocycles, carbon atoms (spiro atoms) belong to two rings simultaneously. When a heterocyclyl is substituted, the substitution can occur, independently of one another, in mono- or polysubstituted form on each of all carbon and / or nitrogen atoms that carry hydrogen. Heterocyclyl itself can be linked to the molecule as a substituent via all suitable positions of the ring system. When the heterocyclyl has a nitrogen atom, the preferred position for attaching the heterocyclyl substituent to the molecule is the nitrogen atom.

  Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, morpholinyl, diazepanyl, diazepanyl, morpholinyl. Homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1.4] -oxazepanyl, tetrahydrothienyl, homothio Morpholinyl-S, S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, Hydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S, S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet -Pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-azabicyclo [3.2.1] octyl, 8-azabicyclo [5.1.0] octyl, 2-oxa-5-azabicyclo [2. 2.1] heptyl, 8-oxa-3-aza-bicyclo [3.2.1] octyl, 3,8-diaza-bicyclo [3.2.1] octyl, 2,5-diaza-bicyclo [2. 2.1] heptyl, 1-aza-bicyclo [2.2.2] octyl, 3,8-diaza-bicyclo [3.2.1] octyl 3,9-diaza-bicyclo [4.2.1] nonyl, 2,6-diaza-bicyclo [3.2.2] nonyl, 1,4-dioxa-spiro [4.5] decyl, 1-oxa- 3,8-diaza-spiro [4.5] decyl, 2,6-diaza-spiro [3.3] heptyl, 2,7-diaza-spiro [4.4] nonyl, 2,6-diaza-spiro [ 3.4] octyl, 3,9-diaza-spiro [5.5] undecyl, 2,8-diaza-spiro [4.5] decyl and the like.

A further example is the structure illustrated below, which can be linked via (in exchange for) hydrogen, each atom carrying a hydrogen:

The above definition for heterocyclyl also applies when the heterocyclyl is part of another group, for example heterocyclylamino or heterocyclyloxy.
When the free valence of the heterocyclyl is saturated, a heterocyclic group is obtained.
The term heterocyclylene is also derived from the previously defined heterocyclyl.

である。
ヘテロシクリレンに関する上記の定義は、例えばＨＯ−ヘテロシクリレンアミノまたはＨ₂Ｎ−ヘテロシクリレンオキシのように、ヘテロシクリレンが別の基の一部である場合にも適用される。 Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example

It is.
The above definition for heterocyclylene also applies when the heterocyclylene is part of another group, for example HO-heterocyclyleneamino or H ₂ N-heterocyclyleneoxy.

  Heteroaryl is one or more identically selected independently of one another from nitrogen, sulfur and oxygen, instead of one or more carbon atoms, as compared to the corresponding aryl or cycloalkyl (cycloalkenyl) Or means a monocyclic heteroaromatic or polycyclic ring having at least one heteroaromatic ring containing different heteroatoms, where the resulting groups must be chemically stable. Necessary items for the presence of heteroaryl are heteroatoms and heteroaromatic systems. If the heteroaryl is substituted, the substitution can occur, independently of one another, in mono- or poly-substituted forms on each of all carbon and / or nitrogen atoms that carry hydrogen. The heteroaryl itself can be linked as a substituent to the molecule via all suitable positions of the ring system, both carbon and nitrogen.

  Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl- N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N- Oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzo Enyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazolidyl Benzoxazolyl, pyridopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl- N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxy , Benzimidazolyl -N- oxide and the like.

Further examples are the structures illustrated below, which can each be added via atoms carrying hydrogen (in exchange for hydrogen):

The above definition for heteroaryl also applies when the heteroaryl is part of another group, for example heteroarylamino or heteroaryloxy.
When the free valence of the heteroaryl is saturated, a heteroaromatic group is obtained.
Thus, the term heteroarylene can be derived from the previously defined heteroaryl.

である。
ヘテロアリーレンに関する上記の定義は、例えばＨＯ−ヘテロアリーレンアミノまたはＨ₂Ｎ−ヘテロアリーレンオキシのように、ヘテロアリーレンが別の基の一部である場合にも適用される。 Heteroarylene, unlike heteroaryl, is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example

It is.
The above definition of heteroarylene, for example HO- as heteroarylene amino or H ₂ N-heteroarylene oxy, heteroarylene is applied to a case that is part of another group.

The aforementioned divalent groups (alkylene, alkenylene, alkynylene, etc.) may also be part of a complex group (eg, H ₂ N—C _1-4 alkylene- or HO—C _1-4 alkylene-). In this case, one of the valence (here, -NH _2, -OH) is bound groups are saturated, as a result, this type of composite groups, denoted in this method, monovalent whole Are only the substituents.
By substituted is meant that a hydrogen atom that is directly bonded to the atom under consideration has been replaced with another atom or another group of atoms (substituent). Depending on the initial conditions (number of hydrogen atoms), mono- or polysubstitution can occur on one atom. Substitution with a particular substituent is such that the permissible valences of the substituent and of the atom to be substituted coincide with each other, and the substitution is stable (ie, for example, rearrangement, cyclization or This is only possible if it results in compounds that are not converted spontaneously by elimination.
In a preferred embodiment, “one or more substituents” refers to “one, two or three substituents”, more preferably “one or two substituents”.

Divalent substituents such as = S, = NR, = NOR, = NNRR, = NN (R) C (O) NRR, = N ₂ can be substituted only with carbon atoms, where The valent substituent = O can also be a substituent at sulfur. Usually, the substitution can only be carried out with a divalent substituent in the ring system and can be replaced by two geminal hydrogen atoms, ie hydrogen atoms bonded to the same carbon atom saturated before substitution. Need. Substitution with divalent substituents is therefore possible only at the ring system group —CH ₂ — or at the sulfur atom.
Stereochemistry / solvates / hydrates:
Structural formulas or chemical names given in the description or in the claims refer to the relevant compounds themselves, unless otherwise specified, but also include tautomers, stereoisomers, optical and geometric isomers (eg enantiomers, diastereomers). Stereomers, E / Z isomers, etc.), racemates, mixtures of individual enantiomers in any desired combination, mixtures of diastereomers, combinations of the forms mentioned previously (if such forms exist), As well as salts, especially pharmaceutically acceptable salts thereof. The compounds and salts according to the invention can exist in solvated forms (eg with water, pharmaceutically acceptable solvents such as ethanol) or in unsolvated forms. In general, for the purposes of the present invention, solvated forms, such as hydrates, are considered equivalent to unsolvated forms.
salt:
The term “pharmaceutically acceptable”, as used herein, is suitable for use in connection with human and / or animal tissue and is Compounds, materials, compositions and those that do not have or cause any toxic, irritation or immune response, or do not cause other problems or difficult situations, i.e. comprehensively corresponding to an acceptable risk / benefit ratio / Or refers to a formulation.

  The term “pharmaceutically acceptable salts” relates to derivatives of the disclosed compounds wherein the parent compound has been modified by the addition of acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, for example, salts with inorganic or organic acids for basic functional groups such as amines and alkali metals; or for acidic functional groups such as carboxylic acids. Contains organic salts. These salts include, among others, acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, ditartrate, bromide / hydrobromide, Ca-edetate / Edetate, camsylate, carbonate, chloride / hydrochloride, citrate, edylate, ethanedisulfonate, estolate, esylate, Fumarate, glucoceptate, gluconate, glutamate, glycolate, glycolylarsanilate, hexyl resorcinate, hydrabamine salt, hydroxymaleate, hydroxynaphthoate, iodide, Isothionate, lactate, lactobi Onnate, malate, maleate, mandelate, methanesulfonate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate , Oxalate, pamonate, pantothenate, phenylacetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, basic acetate, succinate , Sulfamide, sulfate, tannate, tartrate, teocrate, toluenesulfonate, triethiodide, ammonium salt, benzathine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, and Procaine salt is mentioned. Other pharmaceutically acceptable salts can be formed using cations of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc (Pharmaceutical salts, Birge, SM et al., J. (See also Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be prepared by conventional chemical methods, starting from the parent compound bearing an acidic or basic functional group. In general, such salts can be obtained in sufficient amounts of the free acid or base form of these compounds in water or an organic solvent such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof). Can be synthesized by reacting with the corresponding base or acid.
For example, salts of acids other than those described above (eg, trifluoroacetate salts) useful for purifying or isolating compounds from the reaction mixture should also be considered part of this invention.

などの表現において、文字Ａは、例えば、当該環の他の環への結合を示すことをより簡単にするために、環の名称の役割を有する。
二価の基の場合、それらの基がどの隣接基にどの原子価で結合しているかを確定することが決定的に重要であり、明白にする目的のために必要なら、次の表現のように、対応する結合パートナーを括弧で示す：

For example,

In the expressions such as, the letter A has the role of the name of a ring, for example, to make it easier to show the bond of the ring to another ring.
In the case of divalent groups, it is crucial to determine which valences are attached to which adjacent groups, and if necessary for the purpose of clarification, Shows the corresponding binding partner in parentheses:

Groups or substituents are frequently selected among several alternative groups / substituents with corresponding group names (eg, R ^a , R ^b, etc.). When such groups are used repeatedly in different molecular parts to define the compounds according to the invention, it is always noted that the various uses should be considered completely independent of each other. I want to be.

For purposes of the present invention, a therapeutically effective amount means the amount of a substance that is capable of eliminating the symptoms of the disease, or preventing or reducing these symptoms, or prolonging the survival of the patient being treated.

Other features and advantages of the present invention will become apparent from the following more detailed examples, which illustrate, without limitation, the nature of the invention.
General Unless otherwise noted, all reactions are carried out in commercially available equipment using methods commonly used in chemical laboratories. Air and / or moisture sensitive starting materials are stored under a protective gas, and the corresponding reaction and accompanying operations are carried out under a protective gas (nitrogen or argon).
Compounds are named according to the Beilstein rule using Autonom software (Beilstein). If there is a discrepancy when a compound is represented by both the structural formula and its nomenclature, the structural formula prevails.

Chromatography Thin layer chromatography is carried out using Merck ready-made TLC plates (including fluorescent indicator F-254) consisting of silica gel 60 on glass.
Preparative high pressure liquid chromatography (HPLC) of exemplary compounds according to the present invention was performed using a column made by Waters (name: Sunfire C18, 5 μm, 30 × 100 mm, part number 186002572; X-Bridge C18, 5 μm, 30 × 100 mm, part number). 186002982). The compounds are eluted using various gradients of H ₂ O / acetonitrile or H ₂ O / MeOH, where 0.1% HCOOH is added to the water to make it acidic. Chromatography under basic conditions also uses a gradient of H ₂ O / acetonitrile, with water according to the following formulation: 5 mL ammonium bicarbonate solution (158 g / 1 L H ₂ O) and 2 mL ammonia The (7M / MeOH) solution was made basic with 1 L of H ₂ O.

Normal-phase preparative high-pressure liquid chromatography (HPLC) of exemplary compounds according to the present invention includes a column manufactured by Macherey & Nagel (name: Nucleosil, 50-7, 40 × 250 mm) and a column manufactured by VDSoptilab (name: Kromasil 100 NH ₂ , 10 μM). , 50 × 250 mm). The compound is eluted using various gradients of DCM / MeOH (0.1% NH ₃ added to MeOH).
Analytical HPLC (for reaction monitoring) of the intermediate compound is performed using columns from Agilent, Waters and Phenomenex. The analytical device also comprises a mass detector in each case.
HPLC Mass Spectroscopy / UV Spectroscopy Retention time / MS-ESI ⁺ for characterizing exemplary compounds according to the present invention was generated using an Agilent HPLC-MS instrument (high performance liquid chromatography with mass detector). Is done. A retention time tR = 0 is assigned to the compound that elutes at the time of the injection peak.

Analytical Method HPLC: Agilent 1100 Series MS: Agilent LC / MSD SL
Column: Waters, XBridge (TM) C18, 2.5 [mu] m, 2.1 x 20 mm, part number 186003201
Solvent A: 0.1% NH ₃ (= pH 9 to 10)
B: acetonitrile HPLC grade detection: MS: positive and negative
Mass range: 120-800 m / z
Fragmentor: 70
Gain EMV: 1
Threshold: 150
Step size: 0.25
UV: 315 nm
Band width: 170nm
Reference: Off
Range: 230-400nm
Range step: 2.00nm
Peak width: <0.01 min
Slit: 2nm
Injection volume: 5 μL
Flow rate: 1.00 mL / min Column temperature: 60 ° C
Gradient: 0.00 min 5% B
0.00 ~ 2.50 min 5% → 95% B
2.50 to 2.80 minutes 95% B
2.81-3.10 minutes 95% → 5% B

Preparation of the compounds according to the invention The compounds according to the invention are prepared by the synthetic methods described below, in which the substituents of the general formula have the meanings indicated above. These methods are to be construed as illustrative of the invention and are not intended to limit the scope of claimed subject matter and compounds to these examples. If the preparation of the starting compounds is not described, they can be purchased or can be prepared analogously to known compounds or the methods described herein. Substances described in the literature are prepared by published synthetic methods.

Unless otherwise specified, the substituents R ^{1 to} R ⁶ and n in the following reaction scheme are as defined in the specification and claims.
Compounds of formula I can be prepared according to the following schemes (1-5):
Scheme 1

One method for the preparation of compounds of formula I starts from an intermediate having formula A ¹ as illustrated in scheme 1. Intermediates having formula A ¹ , where X is bromine or iodine, preferably iodine, can be purchased or prepared by methods well known in the art. In step (i), and trimethylsilyl acetylene intermediate A ^1, a palladium catalyst, preferably bis (triphenylphosphine) palladium (II) chloride, copper-based cocatalyst, preferably iodide (I), and excess organic The reaction is carried out in a solvent containing a base, preferably triethylamine (eg THF, DMF, DMSO, 1,2-dimethoxyethane or dioxane, preferably DMF). The reaction is carried out at an elevated temperature, preferably 60 ° C., for about 1-16 hours, preferably about 3 hours. The product is isolated by conventional means and is preferably purified by chromatography.

The intermediate having formula B is prepared in step (ii) by reacting the product obtained in step (i) with a base, preferably potassium carbonate, in a solvent, preferably MeOH, at room temperature for 3 hours. Is done. Intermediate B is isolated by conventional means and used as such or purified by chromatography.
The intermediate having formula E ¹ is obtained in step (iii) by reacting intermediate B with an intermediate having formula C ^1, where X is bromide or iodide, preferably bromide. It is done. Intermediates having formula C ¹ can be purchased or can be prepared by methods well known in the art. In step (iii), intermediate B is replaced with intermediate C ¹ and a palladium catalyst, preferably bis (triphenylphosphine) palladium (II) chloride, a copper-based cocatalyst, preferably copper (I) iodide, and excess The reaction is carried out in a solvent containing an organic base, preferably triethylamine (eg THF, DMF, DMSO, 1,2-dimethoxyethane or dioxane, preferably DMF). The reaction is carried out at an elevated temperature, preferably 50 ° C. or 75 ° C., for several hours, preferably overnight. Intermediate E ¹ is isolated by conventional means and preferably purified by chromatography.
Compounds of formula I are prepared by reacting intermediate E ¹ with R ⁵ -sulfonyl chloride. R ⁵ -sulfonyl chloride can be purchased or prepared by methods well known in the art. In step (iv), intermediate E ¹ is reacted with R ⁵ -sulfonyl chloride in a solvent containing excess base, preferably pyridine, preferably DCM, overnight at room temperature. Compound I is isolated by conventional means and preferably purified by chromatography.

中間体Ｅ¹の別の調製方法は、スキーム２に図示したように、中間体Ａ¹の、式Ｄ¹を有する中間体との反応に基づく。中間体Ｄ¹は、当技術分野で周知の方法により調製することができる。中間体Ａ¹を中間体Ｄ¹と、パラジウム触媒、好ましくはテトラキス（トリフェニルホスフィン）パラジウム（０）、銅系助触媒、好ましくはヨウ化銅（Ｉ）、および過剰な有機塩基、好ましくはトリエチルアミンまたはＤＩＰＥＡを含む溶媒（例えば、ＴＨＦ、ＤＭＦ、ＤＭＳＯ、１，２−ジメトキシエタンまたはジオキサン、好ましくはＴＨＦまたはＤＭＳＯ）中で反応させる。反応は、高められた温度、好ましくは４５〜８０℃で、より好ましくは７５℃で、約数時間、好ましくは終夜実施される。中間体Ｅ¹は、通常の手段で単離され、および好ましくはクロマトグラフィーで精製される。中間体Ｅ¹を、上記の方法により式Ｉの化合物に変換することができる。 Scheme 2

Another process for the preparation of Intermediate E ^1, as shown in Scheme 2, intermediates A ^1, based on the reaction of intermediates of formula D ^1. Intermediate D ¹ can be prepared by methods well known in the art. Intermediate A ¹ with intermediate D ¹ and a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium (0), a copper-based cocatalyst, preferably copper (I) iodide, and an excess organic base, preferably triethylamine Alternatively, the reaction is performed in a solvent containing DIPEA (eg, THF, DMF, DMSO, 1,2-dimethoxyethane or dioxane, preferably THF or DMSO). The reaction is carried out at an elevated temperature, preferably 45-80 ° C, more preferably 75 ° C, for about several hours, preferably overnight. Intermediate E ¹ is isolated by conventional means and preferably purified by chromatography. Intermediate E ¹ can be converted to a compound of formula I by the methods described above.

式Ｉの化合物の代わりの調製方法をスキーム３に図示する。式Ａ²（式中、Ｘは臭素またはヨウ素、好ましくはヨウ素である）を有する中間体は、購入できるか、当技術分野で周知の方法により調製することができる。ステップ（ｉ）において、中間体Ａ²を中間体Ｄ¹と、パラジウム触媒、好ましくはテトラキス（トリフェニルホスフィン）パラジウム（０）、銅系助触媒、好ましくはヨウ化銅（Ｉ）、および過剰な有機塩基、好ましくはジイソプロピルアミンまたはトリエチルアミンを含む溶媒（例えば、ＴＨＦ、ＤＭＦ、ＤＭＳＯ、１，２−ジメトキシエタンまたはジオキサン、好ましくはＤＭＳＯ）中で反応させて、中間体Ｅ²を得る。反応は、高められた温度、好ましくは６０〜６５℃で数時間、好ましくは終夜実施される。中間体Ｅ²は、通常の手段で単離され、および好ましくはクロマトグラフィーで精製される。
中間体Ｅ³は、ステップ（ｉｉ）において、中間体Ｅ²をＲ⁵−スルホニルクロリドと、過剰の塩基、好ましくはピリジンまたはルチジンを含む溶媒、好ましくはＤＣＭ中、室温で終夜反応させることによって得られる。中間体Ｅ³は、通常の手段で単離され、および好ましくはクロマトグラフィーで精製される。 Scheme 3

An alternative method for preparing compounds of formula I is illustrated in Scheme 3. Intermediates having the formula A ² , where X is bromine or iodine, preferably iodine are commercially available or can be prepared by methods well known in the art. In step (i), the intermediate A ² Intermediate D ^1, the palladium catalyst, preferably tetrakis (triphenylphosphine) palladium (0), copper-based cocatalyst, preferably iodide (I), and excess organic base, preferably a solvent containing diisopropylamine or triethylamine (e.g., THF, DMF, DMSO, 1,2-dimethoxyethane or dioxane, preferably DMSO) and reacted in to give intermediate E ^2. The reaction is carried out at an elevated temperature, preferably 60-65 ° C. for several hours, preferably overnight. Intermediate E ² is isolated by conventional means and preferably purified by chromatography.
Intermediate E ³ is obtained in step (ii) by reacting intermediate E ² with R ⁵ -sulfonyl chloride in a solvent containing excess base, preferably pyridine or lutidine, preferably in DCM, overnight at room temperature. It is done. Intermediate E ³ is isolated by conventional means and preferably purified by chromatography.

Compounds of formula I are prepared by reacting intermediate E ³ with amine R ² . Amine R ² can be purchased or prepared by methods well known in the art. In step (iv), intermediate E ^{3 is used} with amine R ² and in solvents such as THF, NMP, dioxane and DMF, preferably dioxane, with or without excess base, preferably triethylamine or diisopropylethylamine. And react. The reaction is carried out at an elevated temperature, 80-130 ° C., preferably 80 ° C. for 1-3 hours, preferably 3 hours. Compound I is isolated by conventional means and preferably purified by chromatography.

代わりの方法では、スキーム４に図示したように、中間体Ｅ²を、中間体Ｅ¹に変換する。中間体Ｅ²をアミンＲ²と、過剰の塩基、好ましくはジイソプロピルエチルアミンを含む溶媒、例えば、ＴＨＦ、ＮＭＰ、ジオキサンおよびＤＭＦ、好ましくはジオキサン中で反応させる。反応は、高められた温度、好ましくは８０℃で数時間、好ましくは終夜実施される。中間体Ｅ¹は、通常の手段で単離され、および好ましくはクロマトグラフィーで精製される。 Scheme 4

In an alternative method, intermediate E ² is converted to intermediate E ¹ as illustrated in Scheme 4. Intermediate E ² is reacted with amine R ² in a solvent containing excess base, preferably diisopropylethylamine, such as THF, NMP, dioxane and DMF, preferably dioxane. The reaction is carried out at an elevated temperature, preferably 80 ° C. for several hours, preferably overnight. Intermediate E ¹ is isolated by conventional means and preferably purified by chromatography.

さらに別の代替方法において、式Ｅ³を有する中間体は、スキーム５に図示したように、中間体Ａ²を中間体Ｄ²と反応させることによって調製される。式Ｄ²を有する中間体は、当技術分野で周知の方法により調製することができる。中間体Ａ²を中間体Ｄ²と、パラジウム触媒、好ましくはテトラキス（トリフェニルホスフィン）パラジウム（０）またはビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド（ｂｉｓ（ｔｒｉｐｈｅｎｙｌｐｈｏｓｐｉｎｅ）ｐａｌｌａｄｉｕｍ（ＩＩ） ｃｈｌｏｒｉｄｅ）、銅系助触媒、好ましくはヨウ化銅（Ｉ）、および過剰な有機塩基、好ましくはトリエチルアミンまたはジイソプロピルアミンを含む溶媒（例えば、ＴＨＦ、ＤＭＦ、ＤＭＳＯ、１，２−ジメトキシエタンまたはジオキサン、好ましくはＴＨＦ、ＤＭＦまたはＤＭＳＯ）中で反応させる。反応は、高められた温度、好ましくは６５℃で約１〜１６時間、好ましくは４時間実施される。中間体Ｅ³は、通常の手段で単離され、および好ましくはクロマトグラフィーで精製される。中間体Ｅ³を、前記の方法により式Ｉの化合物に変換することができる。 Scheme 5

In yet another alternative, an intermediate having formula E ³ is prepared by reacting intermediate A ² with intermediate D ² as illustrated in Scheme 5. Intermediates of formula D ² can be prepared by methods well known in the art. Intermediate A ² with Intermediate D ² and a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium (0) or bis (triphenylphosphine) palladium (II) chloride (bis (triphenylphospine) palladium (II) chloride), Copper-based cocatalyst, preferably copper (I) iodide, and a solvent containing excess organic base, preferably triethylamine or diisopropylamine (eg THF, DMF, DMSO, 1,2-dimethoxyethane or dioxane, preferably THF , DMF or DMSO). The reaction is carried out at an elevated temperature, preferably 65 ° C., for about 1 to 16 hours, preferably 4 hours. Intermediate E ³ is isolated by conventional means and preferably purified by chromatography. Intermediate E ³ can be converted to a compound of formula I by the methods described above.

１００ｇ（０．７０ｍｏｌ）の４−ヒドロキシ−２−メルカプト−６−メチルピリミジンおよび３００ｇのラネーニッケルを水（１０００ｍＬ）に懸濁し、その懸濁液を、還流下で終夜にわたって加熱撹拌する。反応混合物を、セライトを通して濾過し、濾液を減圧下で濃縮して粗生成物を得る。 Preparation of Intermediate A A-1) 6-Methyl-3H-pyrimidin-4-one

100 g (0.70 mol) 4-hydroxy-2-mercapto-6-methylpyrimidine and 300 g Raney nickel are suspended in water (1000 mL) and the suspension is heated and stirred at reflux overnight. The reaction mixture is filtered through celite and the filtrate is concentrated under reduced pressure to give the crude product.

酢酸中の７０ｇ（０．６４ｍｏｌ）のＡ−１に、１２７ｇ（０．５６ｍｏｌ）のＮＩＳを分割して、室温で１５分以内に添加する。反応物を、すべての出発原料が消費されるまで（３０時間）室温で撹拌する。反応混合物を水で希釈し、固形生成物を、濾取し、チオ硫酸ナトリウム水溶液で洗浄して過剰なヨウ素を除去し、真空中で乾燥する。収量：９０ｇ（６０％）。 A-2) 5-Iodo-6-methyl-3H-pyrimidin-4-one

127 g (0.56 mol) NIS is divided into 70 g (0.64 mol) A-1 in acetic acid and added within 15 minutes at room temperature. The reaction is stirred at room temperature until all starting material is consumed (30 hours). The reaction mixture is diluted with water and the solid product is filtered off and washed with aqueous sodium thiosulfate to remove excess iodine and dried in vacuo. Yield: 90 g (60%).

９０ｇ（０．３８ｍｏｌ）のＡ−２と６００ｍＬのＰＯＣｌ₃との混合物を、９０℃で１時間加熱する。反応混合物を減圧下で濃縮し、残留物を砕氷中に注ぎ入れる。沈殿した固体を、濾過して集め、水で洗浄し、真空中で乾燥する。収量：９０ｇ（９３％）。¹H NMR (CDCl₃) δ: 8.7 (s, 1H), 2.8 (s, 3H). TLC (シリカ, DCM中10% MeOH): R_f = 0.85. A-3) 4-Chloro-5-iodo-6-methylpyrimidine

A mixture of 90 g (0.38 mol) A-2 and 600 mL POCl ₃ is heated at 90 ° C. for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is poured into crushed ice. The precipitated solid is collected by filtration, washed with water and dried in vacuo. Yield: 90 g (93%). ¹ H NMR (CDCl ₃ ) δ: 8.7 (s, 1H), 2.8 (s, 3H). TLC (silica, 10% MeOH in DCM): R _f = 0.85.

９０ｇ（０．５８ｍｏｌ）の４−ヒドロキシ−２−メルカプト−６−エチルピリミジンおよび２７０ｇのラネーニッケルを水（１０００ｍＬ）に懸濁し、その懸濁液を、還流下で終夜にわたって加熱撹拌する。反応混合物を、セライトを通して濾過し、濾液を減圧下で濃縮して粗生成物を得る。収量：７０．０ｇ（９８％）。 A-4) 6-Ethyl-3H-pyrimidin-4-one

90 g (0.58 mol) 4-hydroxy-2-mercapto-6-ethylpyrimidine and 270 g Raney nickel are suspended in water (1000 mL) and the suspension is heated and stirred at reflux overnight. The reaction mixture is filtered through celite and the filtrate is concentrated under reduced pressure to give the crude product. Yield: 70.0 g (98%).

酢酸中の７０ｇ（０．５６ｍｏｌ）のＡ−４に、１２７ｇ（０．５６ｍｏｌ）のＮＩＳを分割して、室温で１５分以内に添加する。反応物を、すべての出発原料が消費されるまで（３０時間）室温で撹拌する。反応混合物を水で希釈し、固形生成物を、濾取し、チオ硫酸ナトリウム水溶液で洗浄して過剰なヨウ素を除去し、真空中で乾燥する。収量：９０ｇ（６４％）。 A-5) 6-Ethyl-5-iodo-3H-pyrimidin-4-one

127 g (0.56 mol) NIS are divided into 70 g (0.56 mol) A-4 in acetic acid and added within 15 minutes at room temperature. The reaction is stirred at room temperature until all starting material is consumed (30 hours). The reaction mixture is diluted with water and the solid product is filtered off and washed with aqueous sodium thiosulfate to remove excess iodine and dried in vacuo. Yield: 90 g (64%).

９０ｇ（０．３６ｍｏｌ）のＡ−５のＰＯＣｌ₃（６００ｍＬ）中懸濁液を、９０℃で１時間加熱する。反応混合物を減圧下で濃縮し、残留物を砕氷中に注ぎ入れる。沈殿した生成物を、濾過して集め、水で洗浄し、真空中で乾燥する。収量：６５ｇ（６７％）。¹H NMR (CDCl₃) δ: 8.7 (s, 1H), 3.0 (四重線, 2H), 1.3 (三重線, 3H). TLC (シリカ, DCM中10% MeOH): R_f = 0.80. A-6) 4-Chloro-6-ethyl-5-iodopyrimidine

A suspension of 90 g (0.36 mol) of A-5 in POCl ₃ (600 mL) is heated at 90 ° C. for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is poured into crushed ice. The precipitated product is collected by filtration, washed with water and dried in vacuo. Yield: 65 g (67%). ¹ H NMR (CDCl ₃ ) δ: 8.7 (s, 1H), 3.0 (quadruple, 2H), 1.3 (triple, 3H). TLC (silica, 10% MeOH in DCM): R _f = 0.80.

酢酸（２００ｍＬ）中の１０．０ｇ（７０ｍｍｏｌ）の４−クロロ−６−メチルピリミジン−２−イルアミンを０℃まで冷却し、１５．７ｇ（７０ｍｍｏｌ）のＮＩＳを添加し、反応混合物を、出発原料の変換が完結するまで（１８時間）室温で撹拌する。５％Ｎａ₂Ｓ₂Ｏ₃および１０％ＮａＨＣＯ₃の水溶液を、混合物が脱色されるまで添加する。形成された沈殿物を、濾取し、水に取り、生じる懸濁液を室温で１時間撹拌する。生成物を、濾取し、真空中、４０℃で乾燥する。収量：１５．２ｇ（８１％）。¹H NMR (CDCl₃) δ: 5.2 (s, 2H), 2.6 (s, 3H). TLC (シリカ, PE中20% EtOAc): R_f = 0.50. A-7) 4-Chloro-5-iodo-6-methylpyrimidin-2-ylamine

10.0 g (70 mmol) of 4-chloro-6-methylpyrimidin-2-ylamine in acetic acid (200 mL) is cooled to 0 ° C., 15.7 g (70 mmol) of NIS is added and the reaction mixture is charged with starting material. Stir at room temperature until conversion is complete (18 hours). An aqueous solution of 5% Na ₂ S ₂ O ₃ and 10% NaHCO ₃ is added until the mixture is decolorized. The formed precipitate is filtered off, taken up in water and the resulting suspension is stirred at room temperature for 1 hour. The product is filtered off and dried at 40 ° C. in vacuo. Yield: 15.2 g (81%). ¹ H NMR (CDCl ₃ ) δ: 5.2 (s, 2H), 2.6 (s, 3H). TLC (silica, 20% EtOAc in PE): R _f = 0.50.

酢酸（１．０Ｌ）中の２５．０ｇ（１５９ｍｍｏｌ）の４−クロロ−６−エチルピリミジン−２−イルアミンを０℃まで冷却し、３６．０ｇ（１５９ｍｍｏｌ）のＮＩＳを一度に添加する。反応混合物を、出発物質の変換が完結するまで（１８時間）室温で撹拌する。５％Ｎａ₂Ｓ₂Ｏ₃および１０％ＮａＨＣＯ₃の水溶液を、混合物が脱色されるまで添加する。形成された沈殿物を、濾取し、水に取り、その懸濁液を室温で６０分間撹拌する。生成物を、濾取し、ジエチルエーテルで洗浄し、真空中、４０℃で乾燥する。収量：４０．３ｇ（９０％）。¹H NMR (DMSO-d6) δ: 7.2 (s, 2H), 2.7 (四重線, 2H), 1.1 (三重線, 3H). HPLC-MS: tR = 1.62分, (M+H)⁺ = 284. A-8) 4-Chloro-6-ethyl-5-iodopyrimidin-2-ylamine

25.0 g (159 mmol) of 4-chloro-6-ethylpyrimidin-2-ylamine in acetic acid (1.0 L) is cooled to 0 ° C. and 36.0 g (159 mmol) of NIS are added in one portion. The reaction mixture is stirred at room temperature until conversion of the starting material is complete (18 hours). An aqueous solution of 5% Na ₂ S ₂ O ₃ and 10% NaHCO ₃ is added until the mixture is decolorized. The formed precipitate is filtered off, taken up in water and the suspension is stirred for 60 minutes at room temperature. The product is filtered off, washed with diethyl ether and dried at 40 ° C. in vacuo. Yield: 40.3 g (90%). ¹ H NMR (DMSO-d6) δ: 7.2 (s, 2H), 2.7 (quadruple, 2H), 1.1 (triple, 3H). HPLC-MS: tR = 1.62 min, (M + H) ⁺ = 284.

１０ｇ（３９ｍｍｏｌ）のＡ−３、４．１ｍＬ（４７ｍｍｏｌ）のモルホリンおよび１６ｇ（１１８ｍｍｏｌ）の炭酸カリウムをアセトニトリルに懸濁し、８０℃で３時間撹拌する。反応混合物を室温まで冷却し、濾過し、濾液を減圧下で濃縮する。収量：１２ｇ（１００％）。 A-9) 4- (5-Iodo-6-methylpyrimidin-4-yl) -morpholine

10 g (39 mmol) A-3, 4.1 mL (47 mmol) morpholine and 16 g (118 mmol) potassium carbonate are suspended in acetonitrile and stirred at 80 ° C. for 3 hours. The reaction mixture is cooled to room temperature, filtered and the filtrate is concentrated under reduced pressure. Yield: 12 g (100%).

４．３４ｇ（１６．２ｍｍｏｌ）のＡ−６、１．６９ｍＬ（１９．４ｍＬ）のモルホリンおよび６．７０ｇ（４８．５ｍｍｏｌ）の炭酸カリウムのアセトニトリル（５０ｍＬ）中混合物を、８０℃で３時間撹拌する。反応混合物を室温まで冷却し、濾過し、濾液を減圧下で濃縮する。収量：３．９９ｇ（７７％）。 A-10) 4- (6-Ethyl-5-iodopyrimidin-4-yl) -morpholine

A mixture of 4.34 g (16.2 mmol) A-6, 1.69 mL (19.4 mL) morpholine and 6.70 g (48.5 mmol) potassium carbonate in acetonitrile (50 mL) was stirred at 80 ° C. for 3 h. To do. The reaction mixture is cooled to room temperature, filtered and the filtrate is concentrated under reduced pressure. Yield: 3.99 g (77%).

アルゴン雰囲気下で、０．２５ｇ（１．３ｍｍｏｌ）のヨウ化銅（Ｉ）および０．３９ｇ（０．５５ミリモル）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリドを、３．９０ｇ（１１．０ｍｍｏｌ）のＡ−１０と１５ｍＬの乾燥ＤＭＦとの混合物に添加する。続いて、１５ｍＬ（１０９ｍｍｏｌ）のトリエチルアミンおよび１．６２ｇ（１６．５ｍｍｏｌ）のトリメチルシリルアセチレンを添加し、反応混合物を６０℃で３時間撹拌する。反応混合物を減圧下で濃縮し、２００ｍＬの水を添加する。反応混合物を２００ｍＬのＤＣＭで２回抽出し、合わせた有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。生成物を、順相クロマトグラフィー（シリカゲル、２〜１８％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：２．４４ｇ（７７％）。 Preparation of Intermediate B B-1) 4- (6-Ethyl-5-trimethylsilanylethynylpyrimidin-4-yl) -morpholine

Under an argon atmosphere, 3.90 g (11. 1 mmol) of 0.25 g (1.3 mmol) of copper (I) iodide and 0.39 g (0.55 mmol) of bis (triphenylphosphine) palladium (II) dichloride. 0 mmol) of A-10 and 15 mL of dry DMF. Subsequently, 15 mL (109 mmol) of triethylamine and 1.62 g (16.5 mmol) of trimethylsilylacetylene are added and the reaction mixture is stirred at 60 ° C. for 3 hours. The reaction mixture is concentrated under reduced pressure and 200 mL of water is added. The reaction mixture is extracted twice with 200 mL DCM and the combined organic phases are washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The product is purified by normal phase chromatography (silica gel, containing _{2~18% MeOH (NH 3 0.1%} ) / DCM). Yield: 2.44 g (77%).

１０ｍＬのＭｅＯＨと４０ｍＬのＴＨＦ中の１．２ｇ（８．４ｍｍｏｌ）のＢ−１と３．５ｇ（２５ｍｍｏｌ）の炭酸カリウムとの混合物を、室温で３時間撹拌する。反応混合物を、水中に注ぎ入れ、ＤＣＭで抽出する。合わせた有機相をＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。収量：０．９０ｇ（４９％）。 B-2) 4- (6-Ethyl-5-ethynylpyrimidin-4-yl) -morpholine

A mixture of 1.2 g (8.4 mmol) B-1 and 3.5 g (25 mmol) potassium carbonate in 10 mL MeOH and 40 mL THF is stirred at room temperature for 3 hours. The reaction mixture is poured into water and extracted with DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. Yield: 0.90 g (49%).

アルゴン雰囲気下で、０．１８ｇ（０．９４ｍｍｏｌ）のヨウ化銅（Ｉ）および０．３３ｇ（０．４７ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリドを、３．２０ｇ（９．４４ｍｍｏｌ）のＡ−９と１５ｍＬの乾燥ＤＭＦとの混合物に添加する。続いて、１３ｍＬ（９４ｍｍｏｌ）のトリエチルアミンおよび１．９９ｍＬ（１４．２ｍｍｏｌ）のトリメチルシリルアセチレンを添加し、反応混合物を６０℃で４時間、そして４０℃で終夜撹拌する。反応混合物を減圧下で濃縮し、２００ｍＬの水を添加する。反応混合物を２００ｍＬのＤＣＭで２回抽出し、合わせた有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。生成物を、逆相クロマトグラフィー（Ｃ１８、１０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１．１５ｇ（４４％）。 B-3) 4- (6-Methyl-5-trimethylsilanylethynylpyrimidin-4-yl) -morpholine

Under an argon atmosphere, 3.20 g (9.44 mmol) of 0.18 g (0.94 mmol) of copper (I) iodide and 0.33 g (0.47 mmol) of bis (triphenylphosphine) palladium (II) dichloride. ) A-9 and 15 mL of dry DMF. Subsequently, 13 mL (94 mmol) of triethylamine and 1.99 mL (14.2 mmol) of trimethylsilylacetylene are added and the reaction mixture is stirred for 4 hours at 60 ° C. and overnight at 40 ° C. The reaction mixture is concentrated under reduced pressure and 200 mL of water is added. The reaction mixture is extracted twice with 200 mL DCM and the combined organic phases are washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The product is purified by reverse phase chromatography (C18, 10-80% acetonitrile / water with 0.1% formic acid). Yield: 1.15 g (44%).

１０ｍＬのＭｅＯＨと４０ｍＬのＴＨＦ中の１．１５ｇ（４．１８ｍｍｏｌ）のＢ−３と１．７３ｇ（１２．５ｍｍｏｌ）の炭酸カリウムとの混合物を、室温で３時間撹拌する。反応混合物を、水中に注ぎ入れ、ＤＣＭで抽出する。合わせた有機相をＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。残留物を、順相クロマトグラフィー（シリカゲル、１〜１５％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：０．８５ｇ（１００％）。 B-4) 4- (5-Ethynyl-6-methylpyrimidin-4-yl) -morpholine

A mixture of 1.15 g (4.18 mmol) of B-3 and 1.73 g (12.5 mmol) of potassium carbonate in 10 mL of MeOH and 40 mL of THF is stirred at room temperature for 3 hours. The reaction mixture is poured into water and extracted with DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The residue is purified by normal phase chromatography (silica gel, containing _{1~15% MeOH (NH 3 0.1%} ) / DCM). Yield: 0.85 g (100%).

表題化合物は、国際公開第２００６／１０３４４９号（中間体２４）に記載のように調製される。２０．２ｇ（８４２ｍｍｏｌ）の水素化ナトリウムと５００ｍＬの乾燥ＴＨＦとの混合物を０℃まで冷却し、３３．７ｇ（２１１ｍｍｏｌ）のマロン酸ジエチルを３０分にわたって滴加する。続いて、２−クロロ−５−ブロモ−３−ニトロピリジン（５０．０ｇ、２１１ｍｍｏｌ）を、反応温度を０℃に維持するように少量に分割して添加する。添加を完結した後、混合物を５０℃まで加熱し２時間撹拌する。反応物を氷水中に注ぎ入れ、生成物をＥｔＯＡｃで抽出する。有機層を分離し、ＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。生成物を、シリカゲルでのクロマトグラフィーにより精製する。収量：５０．０ｇ（６６％）。 Preparation of Intermediate C C-1) 2- (5-Bromo-3-nitropyridin-2-yl) -malonic acid diethyl ester

The title compound is prepared as described in WO 2006/103449 (Intermediate 24). A mixture of 20.2 g (842 mmol) sodium hydride and 500 mL dry THF is cooled to 0 ° C. and 33.7 g (211 mmol) diethyl malonate are added dropwise over 30 minutes. Subsequently, 2-chloro-5-bromo-3-nitropyridine (50.0 g, 211 mmol) is added in small portions so as to maintain the reaction temperature at 0 ° C. After the addition is complete, the mixture is heated to 50 ° C. and stirred for 2 hours. The reaction is poured into ice water and the product is extracted with EtOAc. The organic layer is separated, dried over MgSO ₄ and the solvent is removed under reduced pressure. The product is purified by chromatography on silica gel. Yield: 50.0 g (66%).

表題化合物は、国際公開第２００６／１０３４４９号（中間体２４）に記載のように調製される。Ｃ−１（４０．０ｇ、１１１ｍｍｏｌ）を１１０ｍＬの１Ｎ ＨＣｌ中に取り、反応混合物を還流下で３時間撹拌する。室温まで冷却した後、反応混合物をＤＣＭで抽出し、合わせた有機層を、ＮａＨＣＯ₃飽和水溶液で洗浄し、ＭｇＳＯ₄上で乾燥し、濾過し、溶媒を減圧下で除去する。収量：２０．０ｇ（８３％）。 C-2) 5-Bromo-2-methyl-3-nitropyridine

The title compound is prepared as described in WO 2006/103449 (Intermediate 24). C-1 (40.0 g, 111 mmol) is taken up in 110 mL of 1N HCl and the reaction mixture is stirred at reflux for 3 hours. After cooling to room temperature, the reaction mixture is extracted with DCM, the combined organic layers are washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ , filtered and the solvent is removed under reduced pressure. Yield: 20.0 g (83%).

鉄粉（１５．４ｇ、２７６ｍｍｏｌ）および塩化アンモニウム（１４．８ｇ、２７６ｍｍｏｌ）を、２０．０ｇ（９２．２ｍｍｏｌ）のＣ−２のＥｔＯＨ（１８０ｍＬ）溶液に添加する。混合物を、還流するまで３時間加熱撹拌する。混合物を、セライトを通して濾過し、溶媒を減圧下で蒸発させる。粗生成物を水およびＤＣＭに取り、有機相を分離し、ＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。表題化合物を、シリカゲルでのクロマトグラフィーで精製する。収量：１５．０ｇ（８７％）。 C-3) 5-Bromo-2-methylpyridin-3-yl-amine

Iron powder (15.4 g, 276 mmol) and ammonium chloride (14.8 g, 276 mmol) are added to a solution of 20.0 g (92.2 mmol) of C-2 in EtOH (180 mL). The mixture is heated and stirred for 3 hours until refluxing. The mixture is filtered through celite and the solvent is evaporated under reduced pressure. The crude product is taken up in water and DCM, the organic phase is separated, dried over MgSO ₄ and the solvent is removed under reduced pressure. The title compound is purified by chromatography on silica gel. Yield: 15.0 g (87%).

２０．０ｇ（８４．２ｍｍｏｌ）の５−ブロモ−２−クロロ−３−ニトロピリジンのＭｅＯＨ（５０ｍＬ）溶液を０℃まで冷却し、１５．８ｍＬ（８４．２ｍｍｏｌ）の３０％ＮａＯＭｅ／ＭｅＯＨ溶液を滴加する。混合物を室温で終夜撹拌し、次いで、還流下で２４時間撹拌する。沈殿物を、濾取し、水に懸濁し、その懸濁液を１時間撹拌する。生成物を、濾取し、真空下で６０℃で乾燥する。収量：１８．７ｇ（９５％）。 C-4) 5-Bromo-2-methoxy-3-nitropyridine

20.0 g (84.2 mmol) of 5-bromo-2-chloro-3-nitropyridine in MeOH (50 mL) was cooled to 0 ° C. and 15.8 mL (84.2 mmol) of 30% NaOMe / MeOH solution was added. Add dropwise. The mixture is stirred at room temperature overnight and then stirred at reflux for 24 hours. The precipitate is filtered off and suspended in water and the suspension is stirred for 1 hour. The product is filtered off and dried at 60 ° C. under vacuum. Yield: 18.7 g (95%).

９８５ｍｇ（４．２３ｍｍｏｌ）のＣ−４のＥｔＯＡｃ（１０ｍＬ）溶液を、３．８２ｇ（１６．９ｍｍｏｌ）の塩化錫（ＩＩ）二水和物で処理する。混合物を還流下で３時間撹拌する。室温まで冷却した後、溶媒を減圧下で除去し、粗生成物を９．５ｍＬの２Ｎ ＮａＯＨ水溶液に取る。室温で１時間撹拌した後、ＤＣＭを添加し、混合物を、セライトを通して濾過する。水相をＤＣＭで抽出し、合わせた有機層をＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。粗生成物は、さらなる精製なしで使用することができる。収量：６４７ｍｇ（７５％）。 C-5) 5-Bromo-2-methoxypyridin-3-yl-amine

A solution of 985 mg (4.23 mmol) of C-4 in EtOAc (10 mL) is treated with 3.82 g (16.9 mmol) of tin (II) chloride dihydrate. The mixture is stirred at reflux for 3 hours. After cooling to room temperature, the solvent is removed under reduced pressure and the crude product is taken up in 9.5 mL of 2N aqueous NaOH. After stirring at room temperature for 1 hour, DCM is added and the mixture is filtered through celite. The aqueous phase is extracted with DCM, the combined organic layers are dried over MgSO ₄ and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 647 mg (75%).

２００ｍｇ（１．１ｍｍｏｌ）のＣ−３、１００μＬ（１．３ｍｍｏｌ）のメタンスルホニルクロリド、２５９μＬ（３．２ｍｍｏｌ）のピリジンおよび５ｍＬのＤＣＭからなる混合物を、室温で３時間撹拌する。反応混合物を濾過し、溶媒を減圧下で除去する。粗生成物は、さらなる精製なしに使用することができる。収量：２００ｍｇ（７１％）。 C-6) N- (5-Bromo-2-methylpyridin-3-yl) -methanesulfonamide

A mixture consisting of 200 mg (1.1 mmol) C-3, 100 μL (1.3 mmol) methanesulfonyl chloride, 259 μL (3.2 mmol) pyridine and 5 mL DCM is stirred at room temperature for 3 hours. The reaction mixture is filtered and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 200 mg (71%).

４．００ｇ（２１．４ｍｍｏｌ）のＣ−３、４．３ｍＬ（３２ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリド、５．２ｍＬ（６４ｍｍｏｌ）のピリジンおよび５０ｍＬのＤＣＭからなる混合物を、室温で５時間撹拌する。反応の完結後、溶媒を減圧下で除去し、粗生成物を５０ｍＬの水に取り、１００ｍＬのＤＣＭで２回抽出する。合わせた有機層をＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。粗生成物は、さらなる精製なしで使用することができる。収量：７．８８ｇ（９１％）。 C-7) N- (5-Bromo-2-methylpyridin-3-yl) -2,4-difluorobenzenesulfonamide

A mixture of 4.00 g (21.4 mmol) of C-3, 4.3 mL (32 mmol) of 2,4-difluorobenzenesulfonyl chloride, 5.2 mL (64 mmol) of pyridine and 50 mL of DCM was stirred at room temperature for 5 hours. Stir. After completion of the reaction, the solvent is removed under reduced pressure and the crude product is taken up in 50 mL water and extracted twice with 100 mL DCM. The combined organic layers are dried over MgSO ₄ and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 7.88 g (91%).

２．４０ｇ（１１．８ｍｍｏｌ）のＣ−５、１．１ｍＬ（１４ｍｍｏｌ）のメタンスルホニルクロリド、２．９ｍＬ（３７ｍｍｏｌ）のピリジンおよび４０ｍＬのＤＣＭからなる混合物を、還流下で１時間撹拌する。室温まで冷却した後、５０ｍＬの水を添加し、混合物を室温で１０分間撹拌する。２相を分離し、有機層を５０ｍＬの５％クエン酸水溶液で２回抽出し、次いで減圧下で濃縮する。残留物をシリカゲルでのクロマトグラフィーで精製する。収量：２．５ｇ（７５％）。 C-8) N- (5-Bromo-2-methoxypyridin-3-yl) -methanesulfonamide

A mixture consisting of 2.40 g (11.8 mmol) C-5, 1.1 mL (14 mmol) methanesulfonyl chloride, 2.9 mL (37 mmol) pyridine and 40 mL DCM is stirred under reflux for 1 hour. After cooling to room temperature, 50 mL of water is added and the mixture is stirred at room temperature for 10 minutes. The two phases are separated and the organic layer is extracted twice with 50 mL of 5% aqueous citric acid and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel. Yield: 2.5 g (75%).

１．８０ｇ（８．８ｍｍｏｌ）のＣ−５、２．２９ｍＬ（１７ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリド、１．０７ｍＬ（１３．３ｍｍｏｌ）のピリジンおよび２０ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。１００ｍＬのＤＣＭを添加し、反応混合物を５０ｍＬの１Ｍ ＨＣｌ水溶液で３回抽出する。有機層をＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。固体を、水／ＭｅＣＮに溶解し、逆相クロマトグラフィー（ＲＰ−ｃｈｒｏｍａｔｏｇｒａｐｙ）でさらに精製する。収量：２．９ｇ（８６％）。 C-9) N- (5-Bromo-2-methoxypyridin-3-yl) -2,4-difluorobenzenesulfonamide

A mixture consisting of 1.80 g (8.8 mmol) C-5, 2.29 mL (17 mmol) 2,4-difluorobenzenesulfonyl chloride, 1.07 mL (13.3 mmol) pyridine and 20 mL DCM was added at room temperature. Stir overnight. 100 mL of DCM is added and the reaction mixture is extracted 3 times with 50 mL of 1 M aqueous HCl. The organic layer is dried over MgSO ₄ and the solvent is removed under reduced pressure. The solid is dissolved in water / MeCN and further purified by reverse phase chromatography (RP-chromatography). Yield: 2.9 g (86%).

２２．０ｇ（１１８ｍｍｏｌ）のＣ−３のジイソプロピルアミン（５００ｍＬ）溶液に、アルゴン雰囲気下で撹拌しながら、２．２ｇ（１２ｍｍｏｌ）のＣｕＩおよび４．１３ｇ（５．９ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリドを添加する。次いで、４８．８ｍＬ（３４８ｍｍｏｌ）のトリメチルシリルアセチレンを添加し、混合物を１００℃で終夜加熱する。通常的な後処理の後、粗生成物をシリカゲルでのカラムクロマトグラフィーで精製する。収量：２３ｇ（９２％）。¹HNMR (CDCl₃) δ: 8.0 (s, 1H), δ 7.0 (s, 1H), 3.6 (s, 2H), 2.4 (s, 3H), 0.1 (s, 9H). TLC (シリカ, PE中50% EtOAc): R_f = 0.50. Preparation of Intermediate D D-10) 2-Methyl-5-trimethylsilanylethynyl-pyridin-3-ylamine

To a solution of 22.0 g (118 mmol) of C-3 in diisopropylamine (500 mL) with stirring under an argon atmosphere, 2.2 g (12 mmol) of CuI and 4.13 g (5.9 mmol) of bis (triphenylphosphine). ) Add palladium (II) chloride. Then 48.8 mL (348 mmol) of trimethylsilylacetylene are added and the mixture is heated at 100 ° C. overnight. After usual work-up, the crude product is purified by column chromatography on silica gel. Yield: 23 g (92%). ¹ HNMR (CDCl ₃ ) δ: 8.0 (s, 1H), δ 7.0 (s, 1H), 3.6 (s, 2H), 2.4 (s, 3H), 0.1 (s, 9H). TLC (silica, in PE 50% EtOAc): R _f = 0.50.

３．５ｇ（９．７ｍｍｏｌ）のＣ−７の乾燥ＴＨＦ（６０ｍＬ）溶液に、アルゴン雰囲気下で撹拌しながら、５６ｍｇ（０．２９ｍｍｏｌ）のＣｕＩ、２０５ｍｇ（０．２９ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド、２５５ｍｇ（０．９７ｍｍｏｌ）のトリフェニルホスフィンおよび１３．５ｍＬ（９７．４ｍｍｏｌ）のトリエチルアミンを添加する。次いで、２．１ｍＬ（１５ｍｍｏｌ）のトリメチルシリルアセチレンを添加し、反応物を６０℃で３日間加熱する。室温まで冷却した後、溶媒を減圧下で除去し、粗生成物をＥｔＯＡｃに取り、水で２回抽出する。合わせた有機層をＭｇＳＯ₄上で乾燥し、生成物を、シリカゲルでのクロマトグラフィーで精製する。収量：３．２０ｇ（８６％）。 D-2) 2,4-Difluoro-N- (2-methyl-5-trimethylsilanylethynyl-pyridin-3-yl) -benzenesulfonamide

To a solution of 3.5 g (9.7 mmol) of C-7 in dry THF (60 mL) with stirring under an argon atmosphere, 56 mg (0.29 mmol) of CuI, 205 mg (0.29 mmol) of bis (triphenylphosphine). ) Palladium (II) chloride, 255 mg (0.97 mmol) triphenylphosphine and 13.5 mL (97.4 mmol) triethylamine are added. 2.1 mL (15 mmol) of trimethylsilylacetylene is then added and the reaction is heated at 60 ° C. for 3 days. After cooling to room temperature, the solvent is removed under reduced pressure and the crude product is taken up in EtOAc and extracted twice with water. The combined organic layers are dried over MgSO ₄ and the product is purified by chromatography on silica gel. Yield: 3.20 g (86%).

２３ｇ（１１３ｍｍｏｌ）のＤ−１のメタノール（２３０ｍＬ）溶液に３１ｇ（２２５ｍｍｏｌ）の炭酸カリウムを撹拌しながら添加し、反応混合物を室温で３時間撹拌する。反応混合物を濾過し、溶媒を減圧下で除去する。粗生成物は、さらなる精製なしで使用することができる。収量：１１ｇ（７４％）。¹H NMR (CDCl₃) δ: 8.1 (s, 1H), δ 7.0 (s, 1H), 3.6 (s, 2H), 3.1 (s, 1H), 2.4 (s, 3H). D-3) 5-Ethynyl-2-methylpyridin-3-ylamine

To a solution of 23 g (113 mmol) of D-1 in methanol (230 mL) is added 31 g (225 mmol) of potassium carbonate with stirring and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 11 g (74%). ¹ H NMR (CDCl ₃ ) δ: 8.1 (s, 1H), δ 7.0 (s, 1H), 3.6 (s, 2H), 3.1 (s, 1H), 2.4 (s, 3H).

０℃の２６ｇ（０．１９７ｍｏｌ）のＤ−３のＴＨＦ（２５０ｍＬ）溶液に、撹拌しながら、４８ｍＬ（０．５９ｍｏｌ）のピリジンを添加する。１０分後に、６８．５ｇ（３９３．４ｍｍｏｌ）の無水メシル酸を添加し、混合物を０℃で３０分間撹拌する。反応混合物を氷水中に注ぎ入れ、ＥｔＯＡｃで抽出する。有機層をＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。得られた生成物をエーテルで洗浄する。収量：２０ｇ（４８％）。 D-4) N- (5-ethynyl-2-methylpyridin-3-yl) -methanesulfonamide

To a solution of 26 g (0.197 mol) of D-3 in THF (250 mL) at 0 ° C., 48 mL (0.59 mol) of pyridine is added with stirring. After 10 minutes, 68.5 g (393.4 mmol) of mesylic anhydride is added and the mixture is stirred at 0 ° C. for 30 minutes. The reaction mixture is poured into ice water and extracted with EtOAc. The organic layer is dried over MgSO ₄ and the solvent is removed under reduced pressure. The product obtained is washed with ether. Yield: 20 g (48%).

３．２０ｇ（８．４ｍｍｏｌ）のＤ−２と１．８１ｇ（８．４ｍｍｏｌ）の炭酸カリウムとのＭｅＯＨ（１０ｍＬ）中混合物を、室温で５時間撹拌する。反応混合物を減圧下で濃縮し、残留物をＥｔＯＡｃに取り、水、１Ｍ ＨＣｌ水溶液およびブラインで洗浄する。有機層をＭｇＳＯ₄上で乾燥し、生成物をシリカゲルでのクロマトグラフィーで精製する。収量：１．８ｇ（６９％）。 D-5) N- (5-ethynyl-2-methylpyridin-3-yl) -2,4-difluorobenzenesulfonamide

A mixture of 3.20 g (8.4 mmol) D-2 and 1.81 g (8.4 mmol) potassium carbonate in MeOH (10 mL) is stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is taken up in EtOAc and washed with water, 1M aqueous HCl and brine. The organic layer is dried over MgSO ₄ and the product is purified by chromatography on silica gel. Yield: 1.8 g (69%).

２．００ｇ（１５．１ｍｍｏｌ）のＤ−３、４．００ｍＬ（２２．７ｍｍｏｌ）のベンゼンスルホニルクロリド、１．８３ｍＬ（２２．７ｍｍｏｌ）のピリジンおよび４５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。ＤＣＭ（５０ｍＬ）を添加し、混合物を５０ｍＬのＫＨＳＯ₄水溶液で抽出する。抽出中に、生成物が沈殿し、それを濾取する。粗生成物は、さらなる精製なしで使用することができる。収量：３．６７ｇ（８９％）。 D-6) N- (5-ethynyl-2-methylpyridin-3-yl) -benzenesulfonamide

A mixture of 2.00 g (15.1 mmol) D-3, 4.00 mL (22.7 mmol) benzenesulfonyl chloride, 1.83 mL (22.7 mmol) pyridine and 45 mL DCM is stirred at room temperature overnight. . DCM (50 mL) is added and the mixture is extracted with 50 mL of aqueous KHSO ₄ solution. During extraction, the product precipitates and is filtered off. The crude product can be used without further purification. Yield: 3.67 g (89%).

２．００ｇ（１５．１ｍｍｏｌ）のＤ−３、４．４２ｍＬ（２２．６ｍｍｏｌ）の２−フルオロベンゼンスルホニルクロリド、１．８３ｍＬ（２２．６ｍｍｏｌ）のピリジンおよび４５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。ＤＣＭ（５０ｍＬ）を添加し、反応混合物を５０ｍＬのＫＨＳＯ₄水溶液で抽出する。抽出中に、生成物が沈殿し、それを濾取する。粗生成物は、さらなる精製なしで使用することができる。収量：３．１０ｇ（７１％）。 D-7) N- (5-ethynyl-2-methylpyridin-3-yl) -2-fluorobenzenesulfonamide

A mixture consisting of 2.00 g (15.1 mmol) D-3, 4.42 mL (22.6 mmol) 2-fluorobenzenesulfonyl chloride, 1.83 mL (22.6 mmol) pyridine and 45 mL DCM was added at room temperature. Stir overnight. DCM (50 mL) is added and the reaction mixture is extracted with 50 mL of aqueous KHSO ₄ solution. During extraction, the product precipitates and is filtered off. The crude product can be used without further purification. Yield: 3.10 g (71%).

２．０ｇ（１５．１ｍｍｏｌ）のＤ−３、４．００ｍＬ（２２．６ｍｍｏｌ）の４−フルオロベンゼンスルホニルクロリド、１．８３ｍＬ（２２．６ｍｍｏｌ）のピリジンおよび４５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。ＤＣＭ（５０ｍＬ）を添加し、反応混合物を５０ｍＬのＫＨＳＯ₄水溶液で抽出する。抽出中に、生成物が沈殿し、それを濾取する。粗生成物は、さらなる精製なしで使用することができる。収量：２．１２ｇ（４８％）。 D-8) N- (5-ethynyl-2-methylpyridin-3-yl) -4-fluorobenzenesulfonamide

A mixture consisting of 2.0 g (15.1 mmol) D-3, 4.00 mL (22.6 mmol) 4-fluorobenzenesulfonyl chloride, 1.83 mL (22.6 mmol) pyridine and 45 mL DCM was added at room temperature. Stir overnight. DCM (50 mL) is added and the reaction mixture is extracted with 50 mL of aqueous KHSO ₄ solution. During extraction, the product precipitates and is filtered off. The crude product can be used without further purification. Yield: 2.12 g (48%).

７．２３ｇ（４１．８ｍｍｏｌ）の５−ブロモ−３−アミノピリジンと７０ｍＬの乾燥ＴＨＦとの混合物に、アルゴン雰囲気下で２３９ｍｇ（１．３ｍｍｏｌ）のＣｕＩ、８８０ｍｇ（１．３ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド、１．１ｇ（４．２ミリモル）のトリフェニルホスフィンおよび７０ｍＬ（０．５０ｍｏｌ）のトリエチルアミンを添加する。次いで、８．３ｍＬ（５９ｍｍｏｌ）のトリメチルシリルアセチレンを添加し、反応混合物を７５℃で終夜加熱する。室温まで冷却した後、１００ｍＬのＤＣＭを添加し、反応混合物を１００ｍＬの水で２回抽出する。有機層をＭｇＳＯ₄上で乾燥し、生成物をシリカゲルでのクロマトグラフィーで精製する。収量：５．２６ｇ（６６％）。 D-9) 5-Trimethylsilanylethynyl-pyridin-3-ylamine

To a mixture of 7.23 g (41.8 mmol) of 5-bromo-3-aminopyridine and 70 mL of dry THF was added 239 mg (1.3 mmol) of CuI, 880 mg (1.3 mmol) of bis (tri) under an argon atmosphere. Phenylphosphine) palladium (II) chloride, 1.1 g (4.2 mmol) of triphenylphosphine and 70 mL (0.50 mol) of triethylamine are added. Then 8.3 mL (59 mmol) of trimethylsilylacetylene is added and the reaction mixture is heated at 75 ° C. overnight. After cooling to room temperature, 100 mL DCM is added and the reaction mixture is extracted twice with 100 mL water. The organic layer is dried over MgSO ₄ and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).

５．２６ｇ（２７．６ｍｍｏｌ）のＢ−１８と７．６３ｇ（０．０５５ｍｏｌ）の炭酸カリウムとのＭｅＯＨ（９０ｍＬ）中混合物を、室温で３０分間撹拌する。反応混合物を減圧下で濃縮し、残留物を５０ｍＬのＤＣＭに取り、５０ｍＬの水で抽出する。有機層をＭｇＳＯ₄上で乾燥し、溶媒を減圧下で除去する。粗生成物は、さらなる精製なしで使用することができる。収量：３．１５ｇ（９６％）。 D-10) 5-Ethynyl-pyridin-3-ylamine

A mixture of 5.26 g (27.6 mmol) B-18 and 7.63 g (0.055 mol) potassium carbonate in MeOH (90 mL) is stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is taken up in 50 mL DCM and extracted with 50 mL water. The organic layer is dried over MgSO ₄ and the solvent is removed under reduced pressure. The crude product can be used without further purification. Yield: 3.15 g (96%).

１．００ｇ（４．９３ｍｍｏｌ）のＣ−５と１５ｍＬの乾燥ＴＨＦとの混合物に、アルゴン雰囲気下で４７ｍｇ（０．２５ｍｍｏｌ）のＣｕＩ、１０４ｍｇ（０．１３ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリドおよび６．８３ｍＬ（４９．３ｍｍｏｌ）のトリエチルアミンを添加する。次いで、１．７４ｍＬ（１２．３ｍｍｏｌ）のトリメチルシリルアセチレンを添加し、反応物を８０℃で終夜加熱する。反応混合物を、室温まで冷却し、濾過し、減圧下で濃縮する。残留物をＤＣＭおよび水に取り、１Ｎ ＨＣｌ水溶液でｐＨ６まで酸性とし、相を分離する。水相をＤＣＭで２回抽出し、合わせた有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。生成物を、順相クロマトグラフィー（シリカゲル、２〜２０％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：０．６９ｇ（６４％）。 D-11) 2-Methoxy-5-trimethylsilanylethynyl-pyridin-3-ylamine

To a mixture of 1.00 g (4.93 mmol) C-5 and 15 mL dry THF was added 47 mg (0.25 mmol) CuI, 104 mg (0.13 mmol) bis (triphenylphosphine) palladium (under argon atmosphere). II) Add chloride and 6.83 mL (49.3 mmol) of triethylamine. Then 1.74 mL (12.3 mmol) of trimethylsilylacetylene is added and the reaction is heated at 80 ° C. overnight. The reaction mixture is cooled to room temperature, filtered and concentrated under reduced pressure. The residue is taken up in DCM and water, acidified with 1N aqueous HCl to pH 6 and the phases are separated. The aqueous phase is extracted twice with DCM and the combined organic phases are washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The product is purified by normal phase chromatography (silica gel, 2 to 20% MeOH (containing _{NH 3 0.1%) / DCM)} . Yield: 0.69 g (64%).

０．９６ｇ（３．１ｍｍｏｌ）のＤ−１１と０．６５ｇ（４．７ｍｍｏｌ）の炭酸カリウムとのＭｅＯＨ（７ｍＬ）中混合物を、室温で２時間撹拌する。次に、１ｍＬの４Ｍ ＨＣｌ／ジオキサンを添加し、反応混合物を減圧下で濃縮する。残留物をＤＣＭおよびＮａＨＣＯ₃飽和水溶液に取り、相を分離し、水相をＤＣＭで抽出する。合わせた有機相をＭｇＳＯ₄上で乾燥し、１ｍＬの４Ｍ ＨＣｌ／ジオキサン溶液を添加し、溶媒を減圧下で除去する。収量：０．５５ｇ（９５％）。 D-12) 5-Ethynyl-2-methoxypyridin-3-ylamine

A mixture of 0.96 g (3.1 mmol) D-11 and 0.65 g (4.7 mmol) potassium carbonate in MeOH (7 mL) is stirred at room temperature for 2 hours. Next, 1 mL of 4M HCl / dioxane is added and the reaction mixture is concentrated under reduced pressure. The residue is taken up in DCM and saturated aqueous NaHCO ₃ , the phases are separated and the aqueous phase is extracted with DCM. The combined organic phases are dried over MgSO ₄ , 1 mL of 4M HCl / dioxane solution is added and the solvent is removed under reduced pressure. Yield: 0.55 g (95%).

乾燥ＴＨＦ（４０ｍＬ）中の５．００ｇ（１８．６ｍｍｏｌ）のＡ−６に、アルゴン雰囲気下で、３５５ｍｇ（１．８ｍｍｏｌ）のヨウ化銅（Ｉ）、２．１５ｇ（１．８ｍｍｏｌ）のテトラキス（トリフェニルホスフィン）パラジウム（０）および２．４ｍＬ（１６．７ｍｍｏｌ）のトリエチルアミンを添加する。次いで、７．０７ｇ（２４．２ｍｍｏｌ）のＤ−４を添加し、反応物を６５℃で４時間加熱する。反応混合物を室温まで冷却し、５０ｍＬの水を添加し、混合物をＤＣＭで抽出する。有機層をＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。生成物をシリカゲルでのクロマトグラフィーにより精製する。収量：２．３３ｇ（３６％）。 Preparation of Intermediate E E-1) N- [5- (4-Chloro-6-ethylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -methanesulfonamide

To 5.00 g (18.6 mmol) A-6 in dry THF (40 mL) under argon atmosphere, 355 mg (1.8 mmol) copper (I) iodide, 2.15 g (1.8 mmol) tetrakis. (Triphenylphosphine) palladium (0) and 2.4 mL (16.7 mmol) of triethylamine are added. 7.07 g (24.2 mmol) of D-4 is then added and the reaction is heated at 65 ° C. for 4 hours. The reaction mixture is cooled to room temperature, 50 mL of water is added and the mixture is extracted with DCM. The organic layer is dried over MgSO ₄ and concentrated under reduced pressure. The product is purified by chromatography on silica gel. Yield: 2.33 g (36%).

乾燥ＴＨＦ（２ｍＬ）中の１５０ｍｇ（０．５６ｍｍｏｌ）のＡ−６に、アルゴン雰囲気下で、５．３ｍｇ（０．０２８ｍｍｏｌ）のヨウ化銅、３２ｍｇ（０２８μｍｏｌ）のテトラキス（トリフェニルホスフィン）パラジウム（０）および７４μＬ（０．５３ｍｍｏｌ）のトリエチルアミンを添加する。次いで、１８９ｍｇ（０．６２ｍｍｏｌ）のＤ−５を添加し、反応物を６５℃で４時間加熱する。反応混合物を室温まで冷却し、５０ｍＬの水を添加し、混合物をＥｔＯＡｃで抽出する。有機層を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。生成物をシリカゲルでのクロマトグラフィーにより精製する。収量：１９６ｍｇ（７８％）。 E-2) N- [5- (4-Chloro-6-ethylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -2,4-difluorobenzenesulfonamide

150 mg (0.56 mmol) of A-6 in dry THF (2 mL) was added to 5.3 mg (0.028 mmol) of copper iodide, 32 mg (028 μmol) of tetrakis (triphenylphosphine) palladium (under argon atmosphere). 0) and 74 μL (0.53 mmol) of triethylamine are added. 189 mg (0.62 mmol) of D-5 is then added and the reaction is heated at 65 ° C. for 4 hours. The reaction mixture is cooled to room temperature, 50 mL of water is added, and the mixture is extracted with EtOAc. The organic layer is dried over MgSO ₄ and concentrated under reduced pressure. The product is purified by chromatography on silica gel. Yield: 196 mg (78%).

アルゴン雰囲気下で、１．１４ｇ（０．９８ｍｍｏｌ）のテトラキス（トリフェニルホスフィン）パラジウム（０）および１８７ｍｇ（０．９８ｍｍｏｌ）のヨウ化銅（Ｉ）を、５．００ｇ（１９．７ｍｍｏｌ）のＡ−３、３．３８ｇ（２５．５ｍｍｏｌ）のＤ−３および１４．２ｍＬ（９８．３ｍｍｏｌ）のジイソプロピルアミンのＤＭＳＯ（１００ｍＬ）中混合物に添加し、反応混合物を６５℃で終夜撹拌する。反応混合物を１５０ｍＬの水上に注ぎ、ＤＣＭ／ＭｅＯＨで抽出する。合わせた有機相を減圧下で濃縮し、残留物を水と共に磨り潰す。粗生成物を、順相クロマトグラフィー（シリカゲル、２〜２０％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：３．７１ｇ（７３％）。 E-3) 5- (4-Chloro-6-methylpyrimidin-5-ylethynyl) -2-methylpyridin-3-ylamine

Under an argon atmosphere, 1.14 g (0.98 mmol) of tetrakis (triphenylphosphine) palladium (0) and 187 mg (0.98 mmol) of copper (I) iodide were added to 5.00 g (19.7 mmol) of A. -3, 3.38 g (25.5 mmol) of D-3 and 14.2 mL (98.3 mmol) of diisopropylamine in DMSO (100 mL) and the reaction mixture is stirred at 65 ° C. overnight. The reaction mixture is poured onto 150 mL water and extracted with DCM / MeOH. The combined organic phases are concentrated under reduced pressure and the residue is triturated with water. The crude product is purified by normal phase chromatography (silica gel, containing _{2~20% MeOH (NH 3 0.1%} ) / DCM). Yield: 3.71 g (73%).

１．５０ｇ（５．８ｍｍｏｌ）のＥ−３、３．０８ｍＬ（２３．２ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリド、１．９ｍＬ（２４．４ｍｍｏｌ）のピリジンおよび４０ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。反応混合物を減圧下で濃縮し、残留物を逆相クロマトグラフィーで精製する。収量：０．７１ｇ（２８％）。 E-4) N- [5- (4-Chloro-6-methylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -2,4-difluorobenzenesulfonamide

A mixture consisting of 1.50 g (5.8 mmol) E-3, 3.08 mL (23.2 mmol) 2,4-difluorobenzenesulfonyl chloride, 1.9 mL (24.4 mmol) pyridine and 40 mL DCM was Stir overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified by reverse phase chromatography. Yield: 0.71 g (28%).

１．５０ｇ（５．８ｍｍｏｌ）のＥ−３、１．４８ｍＬ（１１．６ｍｍｏｌ）のベンゼンスルホニルクロリド、１．４ｍＬ（１７．４ｍｍｏｌ）のピリジンおよび５０ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（１００ｍＬ）を添加し、反応混合物をＤＣＭで３回抽出する。合わせた有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。残留物を逆相クロマトグラフィー（シリカゲル、２〜８％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：１．８０ｇ（７８％）。 E-5) N- [5- (4-Chloro-6-methylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -benzenesulfonamide

A mixture of 1.50 g (5.8 mmol) E-3, 1.48 mL (11.6 mmol) benzenesulfonyl chloride, 1.4 mL (17.4 mmol) pyridine and 50 mL DCM is stirred at room temperature overnight. . Water (100 mL) is added and the reaction mixture is extracted 3 times with DCM. The combined organic phases are washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography purification (silica gel, 2 to 8% MeOH (containing _{NH 3 0.1%) / DCM)} . Yield: 1.80 g (78%).

アルゴン雰囲気下で、２．８６ｇ（９．３７ｍｍｏｌ）のＡ−９、１．５５ｇ（１３．１ｍｍｏｌ）のＤ−１０、５４ｍｇ（０．２８ｍｍｏｌ）のヨウ化銅（Ｉ）、０．２５ｇ（０．９４ｍｍｏｌ）のトリフェニルホスフィン、０．２０ｇ（０．２８ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリドおよび１５．６ｍＬ（１１２ｍｍｏｌ）のトリエチルアミンの乾燥ＴＨＦ（１５ｍＬ）中混合物を、７５℃で終夜撹拌する。反応混合物を室温まで冷却し、１００ｍＬのＤＣＭおよび１００ｍＬの水を添加する。相を分離し、有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。残留物を逆相クロマトグラフィー（シリカゲル、２〜１５％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：１．１２ｇ（４１％）。 E-6) 5- (4-Methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine

Under an argon atmosphere, 2.86 g (9.37 mmol) of A-9, 1.55 g (13.1 mmol) of D-10, 54 mg (0.28 mmol) of copper (I) iodide, 0.25 g (0 .94 mmol) triphenylphosphine, 0.20 g (0.28 mmol) bis (triphenylphosphine) palladium (II) chloride and 15.6 mL (112 mmol) triethylamine in dry THF (15 mL) at 75 ° C. Stir overnight. Cool the reaction mixture to room temperature and add 100 mL DCM and 100 mL water. The phases are separated and the organic phase is washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography purification (silica gel, 2 to 15% MeOH (containing _{NH 3 0.1%) / DCM)} . Yield: 1.12 g (41%).

アルゴン雰囲気下で、７８ｍｇ（０．４１ｍｍｏｌ）のヨウ化銅（Ｉ）および０．４４ｇ（０．６３ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリドを、１．５９ｇ（７．８５ｍｍｏｌ）のＢ−２と５ｍＬの乾燥ＤＭＦとの混合物に添加する。続いて、５．７ｍＬ（４１ｍｍｏｌ）のトリエチルアミンおよび０．９０ｇ（４．１ｍｍｏｌ）のＣ−５を添加し、反応混合物を５０℃で終夜撹拌する。反応混合物を水上に注ぎ、ＥｔＯＡｃで２回抽出する。合わせた有機相を減圧下で濃縮し、生成物をクロマトグラフィーで精製する。収量：０．１５ｇ（１１％）。 E-7) 5- (4-Ethyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -2-methoxypyridin-3-ylamine

Under an argon atmosphere, 78 mg (0.41 mmol) of copper (I) iodide and 0.44 g (0.63 mmol) of bis (triphenylphosphine) palladium (II) dichloride were added in 1.59 g (7.85 mmol). Add to a mixture of B-2 and 5 mL of dry DMF. Subsequently, 5.7 mL (41 mmol) of triethylamine and 0.90 g (4.1 mmol) of C-5 are added and the reaction mixture is stirred at 50 ° C. overnight. The reaction mixture is poured onto water and extracted twice with EtOAc. The combined organic phases are concentrated under reduced pressure and the product is purified by chromatography. Yield: 0.15 g (11%).

アルゴン雰囲気下で、０．３４ｇ（０．４８ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド、９２ｍｇ（０．４８ｍｍｏｌ）のヨウ化銅（Ｉ）および６．７ｍＬ（４８ｍｍｏｌ）のトリエチルアミンを、１．３０ｇ（４．８４ｍｍｏｌ）のＡ−６と約１０ｍＬのＤＭＦとの混合物に添加する。続いて、２．１１ｇ（７．２６ｍｍｏｌ）のＤ−８と約５ｍＬのＤＭＦとの混合物を添加し、反応混合物を６５℃で終夜撹拌する。水を添加し、反応混合物をＤＣＭで抽出する。合わせた有機相を減圧下で濃縮し、残留物を順相クロマトグラフィーで精製する。収量：０．８８ｇ（４２％）。 E-8) N- [5- (4-Chloro-6-ethylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -4-fluorobenzenesulfonamide

Under an argon atmosphere, 0.34 g (0.48 mmol) of bis (triphenylphosphine) palladium (II) chloride, 92 mg (0.48 mmol) of copper (I) iodide and 6.7 mL (48 mmol) of triethylamine were Add to a mixture of 1.30 g (4.84 mmol) of A-6 and about 10 mL of DMF. Subsequently, a mixture of 2.11 g (7.26 mmol) of D-8 and about 5 mL of DMF is added and the reaction mixture is stirred at 65 ° C. overnight. Water is added and the reaction mixture is extracted with DCM. The combined organic phases are concentrated under reduced pressure and the residue is purified by normal phase chromatography. Yield: 0.88 g (42%).

アルゴン雰囲気下で、０．２８ｇ（０．３９ｍｍｏｌ）のビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロリド、７５ｍｇ（０．３９ｍｍｏｌ）のヨウ化銅（Ｉ）および５．５ｍＬ（３９ｍｍｏｌ）のトリエチルアミンを、１．０４ｇ（５．１２ｍｍｏｌ）のＢ−４と５ｍＬのＤＭＦとの混合物に添加する。続いて、０．８０ｇ（３．９ｍｍｏｌ）のＣ−５を添加し、反応混合物を５０℃で終夜撹拌する。水を添加し、反応混合物を、２Ｎ ＮａＯＨ水溶液で中和し、ＥｔＯＡｃで２回抽出する。合わせた有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。残留物を逆相クロマトグラフィー（Ｃ１８、１５〜８５％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：０．５９ｇ（含有量は約５０％）（２３％）。 E-9) 2-Methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine

Under an argon atmosphere, 0.28 g (0.39 mmol) of bis (triphenylphosphine) palladium (II) chloride, 75 mg (0.39 mmol) of copper (I) iodide and 5.5 mL (39 mmol) of triethylamine Add to a mixture of 1.04 g (5.12 mmol) B-4 and 5 mL DMF. Subsequently 0.80 g (3.9 mmol) of C-5 is added and the reaction mixture is stirred at 50 ° C. overnight. Water is added and the reaction mixture is neutralized with 2N aqueous NaOH and extracted twice with EtOAc. The combined organic phases are washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue is purified by reverse phase chromatography (C18, 15-85% acetonitrile / water with 0.1% formic acid). Yield: 0.59 g (content about 50%) (23%).

アルゴン雰囲気下で、３．８ｍＬ（２６ｍｍｏｌ）のジイソプロピルアミンを、０．４３ｇ（０．３１ｍｍｏｌ）のテトラキス（トリフェニルホスフィン）パラジウム（０）、７１ｍｇ（０．３１ｍｍｏｌ）のヨウ化銅（Ｉ）、１．５０ｇ（５．２９ｍｍｏｌ）のＡ−８および１．４５ｇ（６．９０ｍｍｏｌ）のＤ−４のＤＭＳＯ（３０ｍＬ）中混合物に添加し、反応混合物を６５℃で終夜撹拌する。水を添加し、反応混合物をＤＣＭ／ＭｅＯＨで抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を水と共に磨り潰し、真空中、４０℃で乾燥する。収量：１．８０ｇ（９３％）。 E-10) N- [5- (2-Amino-4-chloro-6-ethylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -methanesulfonamide

Under an argon atmosphere, 3.8 mL (26 mmol) of diisopropylamine was added to 0.43 g (0.31 mmol) of tetrakis (triphenylphosphine) palladium (0), 71 mg (0.31 mmol) of copper (I) iodide, 1.50 g (5.29 mmol) of A-8 and 1.45 g (6.90 mmol) of D-4 in DMSO (30 mL) are added and the reaction mixture is stirred at 65 ° C. overnight. Water is added and the reaction mixture is extracted with DCM / MeOH. The combined organic phases are concentrated under reduced pressure and the crude product is triturated with water and dried at 40 ° C. in vacuo. Yield: 1.80 g (93%).

２０ｍＬのジオキサンと２．５ｍＬのＮＭＰ中の１．５０ｇ（５．８０ｍｍｏｌ）のＥ−３に、０．６１ｍＬ（７．０ｍｍｏｌ）のモルホリンおよび３．０ｍＬ（１７ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を８０℃で終夜撹拌する。反応混合物を室温まで冷却し、減圧下で濃縮する。残留物を水に取り、ＤＣＭで抽出する。合わせた有機相を、水で洗浄し、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を順相クロマトグラフィー（シリカゲル、２〜２０％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：１．５３ｇ（８５％）。 E-11) 2-Methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine

To 1.50 g (5.80 mmol) E-3 in 20 mL dioxane and 2.5 mL NMP, 0.61 mL (7.0 mmol) morpholine and 3.0 mL (17 mmol) diisopropylethylamine were added and the reaction The mixture is stirred at 80 ° C. overnight. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is taken up in water and extracted with DCM. The combined organic phases are washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by normal phase chromatography (silica gel, 2-20% MeOH (containing 0.1% NH ₃ ) / DCM). Yield: 1.53 g (85%).

２００ｍｇ（０．３１ｍｍｏｌ）のＥ−９、７７μＬ（０．６１ｍｍｏｌ）のベンゼンスルホニルクロリド、７８μＬ（０．９７ｍｍｏｌ）のピリジンおよび５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（５ｍＬ）を添加し、反応混合物を５ｍＬのＥｔＯＡｃで２回抽出する。有機層をＭｇＳＯ₄上で乾燥し、粗生成物を逆相クロマトグラフィー（Ｃ１８、１５〜８５％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２１ｍｇ（１５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４６６；ｔＲ＝１．２０分。 Preparation of final compound I I-1) N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 200 mg (0.31 mmol) E-9, 77 μL (0.61 mmol) benzenesulfonyl chloride, 78 μL (0.97 mmol) pyridine and 5 mL DCM is stirred at room temperature overnight. Water (5 mL) is added and the reaction mixture is extracted twice with 5 mL EtOAc. The organic layer is dried over MgSO ₄ and the crude product is purified by reverse phase chromatography (C18, 15-85% acetonitrile / water with 0.1% formic acid). Yield: 21 mg (15%). HPLC-MS: M + H = 466; tR = 1.20 min.

１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１、９０μＬ（０．６５ｍｍｏｌ）の２−フルオロベンゼンスルホニルクロリド、７８μＬ（０．９７ｍｍｏｌ）のピリジンおよび５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２５〜８５％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：５８ｍｇ（３９％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４６８；ｔＲ＝１．０８分。 I-2) 2-Fluoro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 100 mg (0.32 mmol) E-11, 90 μL (0.65 mmol) 2-fluorobenzenesulfonyl chloride, 78 μL (0.97 mmol) pyridine and 5 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 25-85% acetonitrile / water with 0.1% formic acid). Yield: 58 mg (39%). HPLC-MS: M + H = 468; tR = 1.08 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、７４ｍｇ（０．５２ｍｍｏｌ）の１−プロパンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１６ｍｇ（１５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４１６；ｔＲ＝０分。 I-3) Propane-1-sulfonic acid [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture consisting of 80 mg (0.26 mmol) E-11, 74 mg (0.52 mmol) 1-propanesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 16 mg (15%). HPLC-MS: M + H = 416; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、１０７ｍｇ（０．５２ｍｍｏｌ）の３−メトキシベンゼンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：５９ｍｇ（４７％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８０；ｔＲ＝０分。 I-4) 3-Methoxy-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 80 mg (0.26 mmol) E-11, 107 mg (0.52 mmol) 3-methoxybenzenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 59 mg (47%). HPLC-MS: M + H = 480; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、１０９ｍｇ（０．５２ｍｍｏｌ）の２−クロロベンゼンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：３１ｍｇ（２５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８４；ｔＲ＝０分。 I-5) 2-Chloro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 80 mg (0.26 mmol) E-11, 109 mg (0.52 mmol) 2-chlorobenzenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 31 mg (25%). HPLC-MS: M + H = 484; tR = 0 min.

８０ｍｇ（０．２６９ｍｍｏｌ）のＥ−１１、１０１ｍｇ（０．５２ｍｍｏｌ）の３−フルオロベンゼンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：３９ｍｇ（３３％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４６８；ｔＲ＝０分。 I-6) 3-Fluoro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 80 mg (0.269 mmol) E-11, 101 mg (0.52 mmol) 3-fluorobenzenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 39 mg (33%). HPLC-MS: M + H = 468; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、１１０ｍｇ（０．５２ｍｍｏｌ）の２，６−ジフルオロベンゼンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１４ｍｇ（１１％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８６；ｔＲ＝０分。 I-7) 2,6-Difluoro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 80 mg (0.26 mmol) E-11, 110 mg (0.52 mmol) 2,6-difluorobenzenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 14 mg (11%). HPLC-MS: M + H = 486; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、１３２ｍｇ（０．５２ｍｍｏｌ）の２−ブロモベンゼンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：３５ｍｇ（２６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５２８／５３０；ｔＲ＝０分。 I-8) 2-Bromo-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 80 mg (0.26 mmol) E-11, 132 mg (0.52 mmol) 2-bromobenzenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 35 mg (26%). HPLC-MS: M + H = 528/530; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、９４ｍｇ（０．５２ｍｍｏｌ）の１−メチルイミダゾール−４−スルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：３５ｍｇ（３０％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４５４；ｔＲ＝０分。 1-9) 1-methyl-1H-imidazole-4-sulfonic acid [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture of 80 mg (0.26 mmol) E-11, 94 mg (0.52 mmol) 1-methylimidazol-4-sulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. . Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 35 mg (30%). HPLC-MS: M + H = 454; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、９５ｍｇ（０．５２ｍｍｏｌ）の２−チオフェンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：３７ｍｇ（３２％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４５６；ｔＲ＝０分。 I-10) Thiophene-2-sulfonic acid [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture consisting of 80 mg (0.26 mmol) E-11, 95 mg (0.52 mmol) 2-thiophenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 37 mg (32%). HPLC-MS: M + H = 456; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、９９ｍｇ（０．５２ｍｍｏｌ）のｏ−トルエンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：３３ｍｇ（２７％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４６４；ｔＲ＝０．９７分。 I-11) 2-Methyl-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 80 mg (0.26 mmol) E-11, 99 mg (0.52 mmol) o-toluenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 33 mg (27%). HPLC-MS: M + H = 464; tR = 0.97 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、８２ｍｇ（０．５２ｍｍｏｌ）の２−メトキシエタン−１−スルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１９ｍｇ（１７％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４３２；ｔＲ＝０分。 I-12) 2-Methoxy-ethanesulfonic acid [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture of 80 mg (0.26 mmol) E-11, 82 mg (0.52 mmol) 2-methoxyethane-1-sulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM is stirred at room temperature overnight. . Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 19 mg (17%). HPLC-MS: M + H = 432; tR = 0 min.

８０ｍｇ（０．２６ｍｍｏｌ）のＥ−１１、１２７ｍｇ（０．５２ｍｍｏｌ）の２−（トリフルオロメチル）ベンゼンスルホニルクロリド、６３μＬ（０．７８ｍｍｏｌ）のピリジンおよび３ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで２回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２２ｍｇ（１６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５１８；ｔＲ＝０分。 I-13) N- [2-Methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -2-trifluoromethyl-benzenesulfonamide

A mixture of 80 mg (0.26 mmol) E-11, 127 mg (0.52 mmol) 2- (trifluoromethyl) benzenesulfonyl chloride, 63 μL (0.78 mmol) pyridine and 3 mL DCM was stirred at room temperature overnight. To do. Water (2 mL) is added and the reaction mixture is extracted twice with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase chromatography (C18, 20-80% acetonitrile / water with 0.1% formic acid). Yield: 22 mg (16%). HPLC-MS: M + H = 518; tR = 0 min.

６３ｍｇ（０．１５ｍｍｏｌ）のＥ−４、１７μＬ（０．１７ｍｍｏｌ）のピペリジン、２８μＬ（０．１７４ｍｍｏｌ）のジイソプロピルエチルアミン、５００μＬのＮＭＰおよび１ｍＬのジオキサンからなる混合物を、マイクロ波の照射下で８０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、２０〜９０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：７ｍｇ（１０％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８４；ｔＲ＝１．２１分。 I-14) 2,4-Difluoro-N- [2-methyl-5- (4-methyl-6-piperidin-1-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 63 mg (0.15 mmol) E-4, 17 μL (0.17 mmol) piperidine, 28 μL (0.174 mmol) diisopropylethylamine, 500 μL NMP and 1 mL dioxane was stirred at 80 ° C. under microwave irradiation. For 1 hour. The reaction mixture is purified by reverse phase chromatography (C18, 20-90% acetonitrile / water with 0.1% formic acid). Yield: 7 mg (10%). HPLC-MS: M + H = 484; tR = 1.21 min.

６３ｍｇ（０．１５ｍｍｏｌ）のＥ−４、１５μＬ（０．１５ｍｍｏｌ）のイソプロピル−メチル−アミン、５００μＬのＮＭＰおよび１ｍＬのジオキサンからなる混合物を、９０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、１０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：５ｍｇ（７％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４７２；ｔＲ＝１．２１分。 I-15) 2,4-Difluoro-N- {5- [4- (isopropyl-methyl-amino) -6-methylpyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -benzenesulfonamide

A mixture of 63 mg (0.15 mmol) E-4, 15 μL (0.15 mmol) isopropyl-methyl-amine, 500 μL NMP and 1 mL dioxane is stirred at 90 ° C. for 1 hour. The reaction mixture is purified by reverse phase chromatography (C18, 10-80% acetonitrile / water with 0.1% formic acid). Yield: 5 mg (7%). HPLC-MS: M + H = 472; tR = 1.21 min.

６３ｍｇ（０．１５ｍｍｏｌ）のＥ−４、１７ｍｇ（０．１５ｍｍｏｌ）のメチル−（テトラヒドロピラン−４−イル）−アミン、５００μＬのＮＭＰおよび１ｍＬのジオキサンからなる混合物を、９０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、１０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１２ｍｇ（１６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５１４；ｔＲ＝０分。 I-16) 2,4-Difluoro-N- (2-methyl-5- {4-methyl-6- [methyl- (tetrahydropyran-4-yl) -amino] -pyrimidin-5-ylethynyl} -pyridine- 3-yl) -benzenesulfonamide

A mixture of 63 mg (0.15 mmol) E-4, 17 mg (0.15 mmol) methyl- (tetrahydropyran-4-yl) -amine, 500 μL NMP and 1 mL dioxane is stirred at 90 ° C. for 1 hour. . The reaction mixture is purified by reverse phase chromatography (C18, 10-80% acetonitrile / water with 0.1% formic acid). Yield: 12 mg (16%). HPLC-MS: M + H = 514; tR = 0 min.

６３ｍｇ（０．１５ｍｍｏｌ）のＥ−４、１９ｍｇ（０．１５ｍｍｏｌ）の１−ピペラジン−１−イル−エタノン、５００μＬのＮＭＰおよび１ｍＬのジオキサンからなる混合物を、９０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、１０〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２５ｍｇ（３３％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５２７；ｔＲ＝１．０８分。 I-17) N- {5- [4- (4-Acetyl-piperazin-1-yl) -6-methylpyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -2,4-difluorobenzene Sulfonamide

A mixture of 63 mg (0.15 mmol) E-4, 19 mg (0.15 mmol) 1-piperazin-1-yl-ethanone, 500 μL NMP and 1 mL dioxane is stirred at 90 ° C. for 1 hour. The reaction mixture is purified by reverse phase chromatography (C18, 10-80% acetonitrile / water with 0.1% formic acid). Yield: 25 mg (33%). HPLC-MS: M + H = 527; tR = 1.08 min.

６３ｍｇ（０．１５ｍｍｏｌ）のＥ−４、１６μＬ（０．１５ｍｍｏｌ）の１−メチルピペラジン、５００μＬのＮＭＰおよび１ｍＬのジオキサンからなる混合物を、９０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、２０〜９０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１７ｍｇ（２４％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４９９；ｔＲ＝１．１１分。 I-18) 2,4-Difluoro-N- {2-methyl-5- [4-methyl-6- (4-methylpiperazin-1-yl) -pyrimidin-5-ylethynyl] -pyridin-3-yl} -Benzenesulfonamide

A mixture of 63 mg (0.15 mmol) E-4, 16 μL (0.15 mmol) 1-methylpiperazine, 500 μL NMP and 1 mL dioxane is stirred at 90 ° C. for 1 hour. The reaction mixture is purified by reverse phase chromatography (C18, 20-90% acetonitrile / water with 0.1% formic acid). Yield: 17 mg (24%). HPLC-MS: M + H = 499; tR = 1.11 min.

２００ｍｇ（０．６８ｍｍｏｌ）のＥ−６、２３９ｍｇ（１．４ｍｍｏｌ）のベンゼンスルホニルクロリド、１６４μＬ（２．０３ｍｍｏｌ）のピリジンおよび１０ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。反応が完結した後、反応生成物を濾過して粗化合物を得る。粗生成物は、さらなる精製なしで使用することができる。収量：０．２２ｇ（７５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４３６；ｔＲ＝１．０１分。 I-19) N- [5- (4-Methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 200 mg (0.68 mmol) E-6, 239 mg (1.4 mmol) benzenesulfonyl chloride, 164 μL (2.03 mmol) pyridine and 10 mL DCM is stirred at room temperature overnight. After the reaction is complete, the reaction product is filtered to obtain the crude compound. The crude product can be used without further purification. Yield: 0.22 g (75%). HPLC-MS: M + H = 436; tR = 1.01 min.

２００ｍｇ（０．６８ｍｍｏｌ）のＥ−６、１８２μＬ（１．４ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリド、１６４μＬ（２．０３ｍｍｏｌ）のピリジンおよび１０ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。反応が完結した後、反応生成物を濾過して粗化合物を得る。粗生成物を、順相クロマトグラフィー（シリカゲル、０〜１５％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：０．１１ｇ（３３％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４７２；ｔＲ＝１．１２分。 I-20) 2,4-Difluoro-N- [5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 200 mg (0.68 mmol) E-6, 182 μL (1.4 mmol) 2,4-difluorobenzenesulfonyl chloride, 164 μL (2.03 mmol) pyridine and 10 mL DCM is stirred at room temperature overnight. After the reaction is complete, the reaction product is filtered to obtain the crude compound. The crude product is purified by normal phase chromatography (silica gel, containing _{0~15% MeOH (NH 3 0.1%} ) / DCM). Yield: 0.11 g (33%). HPLC-MS: M + H = 472; tR = 1.12 min.

１６０ｍｇ（０．５４ｍｍｏｌ）のＥ−６、１９８ｍｇ（１．１ｍｍｏｌ）の２−チオフェンスルホニルクロリド、１３１μＬ（１．６ｍｍｏｌ）のピリジンおよび４ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。反応が完結した後、反応生成物を濾過して粗化合物を得る。粗生成物を、順相クロマトグラフィー（シリカゲル、０〜１５％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：０．１１ｇ（４７％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４４２；ｔＲ＝０．９７分。 I-21) Thiophene-2-sulfonic acid [5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture consisting of 160 mg (0.54 mmol) E-6, 198 mg (1.1 mmol) 2-thiophenesulfonyl chloride, 131 μL (1.6 mmol) pyridine and 4 mL DCM is stirred at room temperature overnight. After the reaction is complete, the reaction product is filtered to obtain the crude compound. The crude product is purified by normal phase chromatography (silica gel, containing _{0~15% MeOH (NH 3 0.1%} ) / DCM). Yield: 0.11 g (47%). HPLC-MS: M + H = 442; tR = 0.97 min.

１６０ｍｇ（０．５４ｍｍｏｌ）のＥ−６、１９２ｍｇ（１．１ｍｍｏｌ）のピリジン−３−スルホニルクロリド、１３１μＬ（１．６ｍｍｏｌ）のピリジンおよび４ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。反応が完結した後、反応生成物を濾過して粗化合物を得る。粗生成物を、順相クロマトグラフィー（シリカゲル、０〜１５％ＭｅＯＨ（ＮＨ₃を０．１％含む）／ＤＣＭ）で精製する。収量：０．４８ｇ（含有量５０％）（１００％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４３７；ｔＲ＝０．８７分。 I-22) Pyridin-3-sulfonic acid [5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture of 160 mg (0.54 mmol) E-6, 192 mg (1.1 mmol) pyridine-3-sulfonyl chloride, 131 μL (1.6 mmol) pyridine and 4 mL DCM is stirred at room temperature overnight. After the reaction is complete, the reaction product is filtered to obtain the crude compound. The crude product is purified by normal phase chromatography (silica gel, containing _{0~15% MeOH (NH 3 0.1%} ) / DCM). Yield: 0.48 g (content 50%) (100%). HPLC-MS: M + H = 437; tR = 0.87 min.

１６０ｍｇ（０．５４ｍｍｏｌ）のＥ−６、１９６μＬ（１．１ｍｍｏｌ）の１−メチル−１Ｈ−ピラゾール−４−スルホニルクロリド、１３１μＬ（１．６ｍｍｏｌ）のピリジンおよび１０ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。反応が完結した後、反応生成物を濾過して粗化合物を得る。収量：０．１６ｇ（６６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４４０；ｔＲ＝０．８０分。 I-23) 1-Methyl-1H-pyrazole-4-sulfonic acid [5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

A mixture of 160 mg (0.54 mmol) E-6, 196 μL (1.1 mmol) 1-methyl-1H-pyrazole-4-sulfonyl chloride, 131 μL (1.6 mmol) pyridine and 10 mL DCM was added at room temperature. Stir overnight. After the reaction is complete, the reaction product is filtered to obtain the crude compound. Yield: 0.16 g (66%). HPLC-MS: M + H = 440; tR = 0.80 min.

０．２０ｇ（０．６８ｍｍｏｌ）のＥ−６と１０ｍＬのＤＣＭとの混合物に、０．１６ｍＬ（２．０ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で５分間撹拌する。０．１０ｍＬ（１．４ｍｍｏｌ）のメタンスルホニルクロリドを添加し、反応混合物を室温で終夜撹拌する。沈殿した生成物を濾取し、真空中、４０℃で乾燥する。収量：０．１５ｇ（５９％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝３７４；ｔＲ＝０．８０分。 I-24) N- [5- (4-Methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -methanesulfonamide

To a mixture of 0.20 g (0.68 mmol) E-6 and 10 mL DCM is added 0.16 mL (2.0 mmol) pyridine and the reaction mixture is stirred at room temperature for 5 minutes. 0.10 mL (1.4 mmol) of methanesulfonyl chloride is added and the reaction mixture is stirred at room temperature overnight. The precipitated product is filtered off and dried at 40 ° C. in vacuo. Yield: 0.15 g (59%). HPLC-MS: M + H = 374; tR = 0.80 min.

７５ｍｇ（０．２２ｍｍｏｌ）のＥ−７、５９μＬ（０．４４ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリドおよび５６μＬ（０．７１ｍｍｏｌ）のピリジンのＤＣＭ（３ｍＬ）中混合物を、室温で終夜撹拌する。反応混合物を減圧下で濃縮し、残留物を逆相クロマトグラフィー（Ｃ１８、２０〜９０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：５２ｍｇ（４６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５１６；ｔＲ＝１．１７分。 I-25) N- [5- (4-Ethyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -2-methoxypyridin-3-yl] -2,4-difluorobenzenesulfonamide

A mixture of 75 mg (0.22 mmol) E-7, 59 μL (0.44 mmol) 2,4-difluorobenzenesulfonyl chloride and 56 μL (0.71 mmol) pyridine in DCM (3 mL) is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the residue is purified by reverse phase chromatography (C18, 20-90% acetonitrile / water with 0.1% formic acid). Yield: 52 mg (46%). HPLC-MS: M + H = 516; tR = 1.17 min.

７５ｍｇ（０．２２ｍｍｏｌ）のＥ−７、５５μＬ（０．４４ｍｍｏｌ）のベンゼンスルホニルクロリドおよび５６μＬ（０．７１ｍｍｏｌ）のピリジンのＤＣＭ（３ｍＬ）中混合物を、室温で終夜撹拌する。反応混合物を減圧下で濃縮し、残留物を逆相クロマトグラフィー（Ｃ１８、２０〜９０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：６４ｍｇ（６０％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８０；ｔＲ＝１．１３分。 I-26) N- [5- (4-Ethyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -2-methoxypyridin-3-yl] -benzenesulfonamide

A mixture of 75 mg (0.22 mmol) E-7, 55 μL (0.44 mmol) benzenesulfonyl chloride and 56 μL (0.71 mmol) pyridine in DCM (3 mL) is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the residue is purified by reverse phase chromatography (C18, 20-90% acetonitrile / water with 0.1% formic acid). Yield: 64 mg (60%). HPLC-MS: M + H = 480; tR = 1.13 min.

１ｍＬのジオキサン中の８０ｍｇ（０．１９ｍｍｏｌ）のＥ−８に、０．４６ｍＬ（０．９３ｍｍｏｌ）の２．０Ｍジメチルアミン／ＴＨＦ溶液を添加し、反応混合物を８０℃で３時間撹拌する。アセトニトリル／水（１／１）混合物を添加し、反応混合物を逆相クロマトグラフィー（Ｃ１８）で精製する。収量：２５ｍｇ（３１％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４４０；ｔＲ＝１．１２分。 I-27) N- [5- (4-Dimethylamino-6-ethylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -4-fluorobenzenesulfonamide

To 80 mg (0.19 mmol) E-8 in 1 mL dioxane is added 0.46 mL (0.93 mmol) 2.0 M dimethylamine / THF solution and the reaction mixture is stirred at 80 ° C. for 3 h. Acetonitrile / water (1/1) mixture is added and the reaction mixture is purified by reverse phase chromatography (C18). Yield: 25 mg (31%). HPLC-MS: M + H = 440; tR = 1.12 min.

１ｍＬのジオキサン中の８０ｍｇ（０．１９ｍｍｏｌ）のＥ−８に、０．１２ｇ（０．９３ｍｍｏｌ）の１−シクロプロピル−ピペラジンおよび２６μＬ（０．１９ｍｍｏｌ）のトリエチルアミンを添加し、反応混合物を８０℃で３時間撹拌する。アセトニトリル／水（１／１）混合物を添加し、反応混合物を逆相クロマトグラフィー（Ｃ１８）で精製する。収量：４９ｍｇ（５１％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５２１；ｔＲ＝１．２６分。 I-28) N- {5- [4- (4-Cyclopropyl-piperazin-1-yl) -6-ethylpyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -4-fluorobenzenesulfone Amide

To 80 mg (0.19 mmol) of E-8 in 1 mL of dioxane, 0.12 g (0.93 mmol) of 1-cyclopropyl-piperazine and 26 μL (0.19 mmol) of triethylamine were added and the reaction mixture was heated to 80 ° C. For 3 hours. Acetonitrile / water (1/1) mixture is added and the reaction mixture is purified by reverse phase chromatography (C18). Yield: 49 mg (51%). HPLC-MS: M + H = 521; tR = 1.26 min.

２００ｍｇ（含有量は約５０％、０．３１ｍｍｏｌ）のＥ−９、８２μＬ（０．６１ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリド、７８μＬ（０．９７ｍｍｏｌ）のピリジンおよび５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（５ｍＬ）を添加し、反応混合物を８ｍＬのＥｔＯＡｃで３回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相ＨＰＬＣ（Ｃ１８、２５〜８５％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２８ｍｇ（１８％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５０２；ｔＲ＝１．２１分。 I-29) 2,4-Difluoro-N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture consisting of 200 mg (content about 50%, 0.31 mmol) E-9, 82 μL (0.61 mmol) 2,4-difluorobenzenesulfonyl chloride, 78 μL (0.97 mmol) pyridine and 5 mL DCM. Stir at room temperature overnight. Water (5 mL) is added and the reaction mixture is extracted 3 times with 8 mL EtOAc. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase HPLC (C18, 25-85% acetonitrile / water with 0.1% formic acid). Yield: 28 mg (18%). HPLC-MS: M + H = 502; tR = 1.21 min.

１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１、１２６ｍｇ（０．６５ｍｍｏｌ）の４−フルオロベンゼンスルホニルクロリド、７８μＬ（０．９７ｍｍｏｌ）のピリジンおよび５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで３回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相ＨＰＬＣ（Ｃ１８、２５〜８５％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１００ｍｇ（６７％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４６８；ｔＲ＝１．１２分。 I-30) 4-Fluoro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 100 mg (0.32 mmol) E-11, 126 mg (0.65 mmol) 4-fluorobenzenesulfonyl chloride, 78 μL (0.97 mmol) pyridine and 5 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted 3 times with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase HPLC (C18, 25-85% acetonitrile / water with 0.1% formic acid). Yield: 100 mg (67%). HPLC-MS: M + H = 468; tR = 1.12 min.

１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１、１３７ｍｇ（０．６５ｍｍｏｌ）の３，５−ジフルオロベンゼンスルホニルクロリド、７８μＬ（０．９７ｍｍｏｌ）のピリジンおよび５ｍＬのＤＣＭからなる混合物を、室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで３回抽出する。合わせた有機相を減圧下で濃縮し、粗生成物を逆相ＨＰＬＣ（Ｃ１８、２５〜８５％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：９９ｍｇ（６４％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８６；ｔＲ＝１．１８分。 I-31) 3,5-Difluoro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

A mixture of 100 mg (0.32 mmol) E-11, 137 mg (0.65 mmol) 3,5-difluorobenzenesulfonyl chloride, 78 μL (0.97 mmol) pyridine and 5 mL DCM is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted 3 times with 4 mL DCM. The combined organic phases are concentrated under reduced pressure and the crude product is purified by reverse phase HPLC (C18, 25-85% acetonitrile / water with 0.1% formic acid). Yield: 99 mg (64%). HPLC-MS: M + H = 486; tR = 1.18 min.

１ｍＬのジオキサン中の７５ｍｇ（０．２１ｍｍｏｌ）のＥ−１に、１．６ｍＬ（３．２ｍｍｏｌ）の２．０Ｍジメチルアミン／ＴＨＦ溶液を添加し、反応混合物を８０℃で３時間撹拌する。アセトニトリル／水（１／１）混合物を添加し、反応混合物を逆相クロマトグラフィー（Ｃ１８）で精製する。収量：３３ｍｇ（４３％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝３６０；ｔＲ＝０．８９分。 I-32) N- [5- (4-Dimethylamino-6-ethylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -methanesulfonamide

To 75 mg (0.21 mmol) E-1 in 1 mL dioxane is added 1.6 mL (3.2 mmol) 2.0 M dimethylamine / THF solution and the reaction mixture is stirred at 80 ° C. for 3 h. Acetonitrile / water (1/1) mixture is added and the reaction mixture is purified by reverse phase chromatography (C18). Yield: 33 mg (43%). HPLC-MS: M + H = 360; tR = 0.89 min.

１ｍＬのジオキサン中の７５ｍｇ（０．２１ｍｍｏｌ）のＥ−１に、２．１４ｍＬ（４．２８ｍｍｏｌ）の２．０Ｍメチルアミン／ＴＨＦ溶液を添加し、反応混合物を８０℃で３時間撹拌する。アセトニトリル／水（１／１）混合物を添加し、反応混合物を逆相クロマトグラフィー（Ｃ１８）で精製する。収量：６ｍｇ（８％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝３４６；ｔＲ＝０．７７分。 I-33) N- [5- (4-Ethyl-6-methylamino-pyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -methanesulfonamide

To 75 mg (0.21 mmol) E-1 in 1 mL dioxane is added 2.14 mL (4.28 mmol) 2.0 M methylamine / THF solution and the reaction mixture is stirred at 80 ° C. for 3 h. Acetonitrile / water (1/1) mixture is added and the reaction mixture is purified by reverse phase chromatography (C18). Yield: 6 mg (8%). HPLC-MS: M + H = 346; tR = 0.77 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２２ｍｍｏｌ）のＥ−１０に、２８ｍｇ（０．２４ｍｍｏｌ）の４−メトキシピペリジンおよび４５μＬ（０．２６ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２９ｍｇ（３０％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４４５；ｔＲ＝０．９５分。 I-34) N- {5- [2-Amino-4-ethyl-6- (4-methoxypiperidin-1-yl) -pyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -methanesulfone Amide

To 80 mg (0.22 mmol) E-10 in 2 mL dioxane and 1 mL DMF was added 28 mg (0.24 mmol) 4-methoxypiperidine and 45 μL (0.26 mmol) diisopropylethylamine and the reaction mixture Is stirred for 1 hour at 130 ° C. in a microwave oven. The reaction mixture is purified by reverse phase chromatography (C18, 5-70% acetonitrile / water with 0.1% formic acid). Yield: 29 mg (30%). HPLC-MS: M + H = 445; tR = 0.95 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２２ｍｍｏｌ）のＥ−１０に、２４ｍｇ（０．２４ｍｍｏｌ）の４−ヒドロキシピペリジンおよび４５μＬ（０．２６ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２３ｍｇ（２４％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４３１；ｔＲ＝０．８１分。 I-35) N- {5- [2-Amino-4-ethyl-6- (4-hydroxypiperidin-1-yl) -pyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -methanesulfone Amide

To 80 mg (0.22 mmol) E-10 in 2 mL dioxane and 1 mL DMF, 24 mg (0.24 mmol) 4-hydroxypiperidine and 45 μL (0.26 mmol) diisopropylethylamine were added and the reaction mixture Is stirred for 1 hour at 130 ° C. in a microwave oven. The reaction mixture is purified by reverse phase chromatography (C18, 5-70% acetonitrile / water with 0.1% formic acid). Yield: 23 mg (24%). HPLC-MS: M + H = 431; tR = 0.81 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２２ｍｍｏｌ）のＥ−１０に、２０ｍｇ（０．２４ｍｍｏｌ）のピペリジンおよび４５μＬ（０．２６ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜８０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：１９ｍｇ（２１％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４１５；ｔＲ＝１．０１分。 I-36) N- [5- (2-Amino-4-ethyl-6-piperidin-1-ylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -methanesulfonamide

To 80 mg (0.22 mmol) E-10 in 2 mL dioxane and 1 mL DMF, 20 mg (0.24 mmol) piperidine and 45 μL (0.26 mmol) diisopropylethylamine were added and the reaction mixture was added to the micro Stir for 1 hour at 130 ° C. in a wave oven. The reaction mixture is purified by reverse phase chromatography (C18, 5-80% acetonitrile / water with 0.1% formic acid). Yield: 19 mg (21%). HPLC-MS: M + H = 415; tR = 1.01 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１に、４９μＬ（０．６５ｍｍｏｌ）のメタンスルホニルクロリドおよび７８μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（５ｍＬ）を添加し、反応混合物を５ｍＬのＥｔＯＡｃで２回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：４４ｍｇ（３５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝３８８；ｔＲ＝０．９１分。 I-37) N- [2-Methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -methanesulfonamide

To 100 mg (0.32 mmol) E-11 in 5 mL DCM is added 49 μL (0.65 mmol) methanesulfonyl chloride and 78 μL (0.97 mmol) pyridine and the reaction mixture is stirred at room temperature overnight. Water (5 mL) is added and the reaction mixture is extracted twice with 5 mL EtOAc. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 5-70% acetonitrile / water with 0.1% formic acid). Yield: 44 mg (35%). HPLC-MS: M + H = 388; tR = 0.91 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１に、７１μＬ（０．６５ｍｍｏｌ）のイソプロピルスルホニルクロリドおよび７８μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（５ｍＬ）を添加し、反応混合物を５ｍＬのＥｔＯＡｃで２回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：８ｍｇ（６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４１６；ｔＲ＝１．０８分。 I-38) Propane-2-sulfonic acid [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

To 100 mg (0.32 mmol) E-11 in 5 mL DCM is added 71 μL (0.65 mmol) isopropylsulfonyl chloride and 78 μL (0.97 mmol) pyridine and the reaction mixture is stirred at room temperature overnight. Water (5 mL) is added and the reaction mixture is extracted twice with 5 mL EtOAc. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 5-70% acetonitrile / water with 0.1% formic acid). Yield: 8 mg (6%). HPLC-MS: M + H = 416; tR = 1.08 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１に、１１８μＬ（０．６５ｍｍｏｌ）のシクロヘキサンスルホニルクロリドおよび７８μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（５ｍＬ）を添加し、反応混合物を５ｍＬのＥｔＯＡｃで２回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：２４ｍｇ（１６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４５６；ｔＲ＝１．２８分。 I-39) Cyclohexanesulfonic acid [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -amide

To 100 mg (0.32 mmol) E-11 in 5 mL DCM is added 118 μL (0.65 mmol) cyclohexanesulfonyl chloride and 78 μL (0.97 mmol) pyridine and the reaction mixture is stirred at room temperature overnight. Water (5 mL) is added and the reaction mixture is extracted twice with 5 mL EtOAc. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 5-70% acetonitrile / water with 0.1% formic acid). Yield: 24 mg (16%). HPLC-MS: M + H = 456; tR = 1.28 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１に、８１μＬ（０．６５ｍｍｏｌ）のベンゼンスルホニルクロリドおよび７８μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２５〜８５％ＭｅＯＨ／水（ＮＨ₃ＯＨを２．５％、ＮＨ₄ＨＣＯ₃を２．５％含む））で精製する。収量：９６ｍｇ（６６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４５０；ｔＲ＝１．０５分。 I-40) N- [2-Methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

To 100 mg (0.32 mmol) E-11 in 5 mL DCM is added 81 μL (0.65 mmol) benzenesulfonyl chloride and 78 μL (0.97 mmol) pyridine and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 25-85% MeOH / water (2.5% NH ₃ OH, 2.5% NH ₄ HCO ₃ )). Yield: 96 mg (66%). HPLC-MS: M + H = 450; tR = 1.05 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３２ｍｍｏｌ）のＥ−１１に、８６μＬ（０．６５ｍｍｏｌ）の２，４−ジフルオロベンゼンスルホニルクロリドおよび７８μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２５〜８５％ＭｅＯＨ／水（ＮＨ₃ＯＨを２．５％、ＮＨ₄ＨＣＯ₃を２．５％含む））で精製する。収量：３５ｍｇ（２２％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４８６；ｔＲ＝１．１４分。 I-41) 2,4-Difluoro-N- [2-methyl-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

To 100 mg (0.32 mmol) E-11 in 5 mL DCM was added 86 μL (0.65 mmol) 2,4-difluorobenzenesulfonyl chloride and 78 μL (0.97 mmol) pyridine and the reaction mixture was allowed to Stir overnight. Water (2 mL) is added and the reaction mixture is extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 25-85% MeOH / water (2.5% NH ₃ OH, 2.5% NH ₄ HCO ₃ )). Yield: 35 mg (22%). HPLC-MS: M + H = 486; tR = 1.14 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２３ｍｍｏｌ）のＥ−１に、２９ｍｇ（０．２５ｍｍｏｌ）の４−メチルピペリジン−４−オールおよび４７μＬ（０．２７ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））続いて、順相クロマトグラフィー（ＮＨ₂でキャップしたシリカ、１〜２０％ＭｅＯＨ／ＤＣＭ）で精製する。収量：２ｍｇ（２％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４３０；ｔＲ＝０．９６分。 I-42) N- {5- [4-Ethyl-6- (4-hydroxy-4-methylpiperidin-1-yl) -pyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -methanesulfone Amide

To 80 mg (0.23 mmol) E-1 in 2 mL dioxane and 1 mL DMF was added 29 mg (0.25 mmol) 4-methylpiperidin-4-ol and 47 μL (0.27 mmol) diisopropylethylamine. The reaction mixture is stirred for 1 hour at 130 ° C. in a microwave oven. Reaction mixture was reverse phase chromatographed (C18, 5-70% acetonitrile / water with 0.1% formic acid) followed by normal phase chromatography (NH ₂ capped silica, 1-20% MeOH / DCM). Purify with. Yield: 2 mg (2%). HPLC-MS: M + H = 430; tR = 0.96 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２２ｍｍｏｌ）のＥ−１０に、２８ｍｇ（０．２４ｍｍｏｌ）の４−メチルピペリジン（ｐｉｐｅｒｄｉｎ）−４−オールおよび４５μＬ（０．２６ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））で精製する。収量：４５ｍｇ（４６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４４５；ｔＲ＝０．９１分。 I-43) N- {5- [2-Amino-4-ethyl-6- (4-hydroxy-4-methylpiperidin-1-yl) -pyrimidin-5-ylethynyl] -2-methylpyridin-3-yl } -Methanesulfonamide

To 80 mg (0.22 mmol) E-10 in 2 mL dioxane and 1 mL DMF, 28 mg (0.24 mmol) 4-methylpiperdin-4-ol and 45 μL (0.26 mmol) diisopropyl. Ethylamine is added and the reaction mixture is stirred in a microwave oven at 130 ° C. for 1 hour. The reaction mixture is purified by reverse phase chromatography (C18, 5-70% acetonitrile / water with 0.1% formic acid). Yield: 45 mg (46%). HPLC-MS: M + H = 445; tR = 0.91 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２３ｍｍｏｌ）のＥ−１に、２１ｍｇ（０．２５ｍｍｏｌ）のピペリジン（ｐｉｐｅｒｄｉｎｅ）および４７μＬ（０．２７ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ギ酸を０．１％含む））続いて、順相クロマトグラフィー（ＮＨ₂でキャップしたシリカ、１〜２０％ＭｅＯＨ／ＤＣＭ）で精製する。収量：３ｍｇ（３％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４００；ｔＲ＝１．１６分。 I-44) N- [5- (4-Ethyl-6-piperidin-1-ylpyrimidin-5-ylethynyl) -2-methylpyridin-3-yl] -methanesulfonamide

To 80 mg (0.23 mmol) E-1 in 2 mL dioxane and 1 mL DMF was added 21 mg (0.25 mmol) piperidine and 47 μL (0.25 mmol) diisopropylethylamine and the reaction mixture Is stirred for 1 hour at 130 ° C. in a microwave oven. Reaction mixture was reverse phase chromatographed (C18, 5-70% acetonitrile / water with 0.1% formic acid) followed by normal phase chromatography (NH ₂ capped silica, 1-20% MeOH / DCM). Purify with. Yield: 3 mg (3%). HPLC-MS: M + H = 400; tR = 1.16 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２３ｍｍｏｌ）のＥ−１に、２９ｍｇ（０．２５ｍｍｏｌ）の４−メトキシピペリジン（ｍｅｔｈｏｘｙｐｉｐｅｒｄｉｎｅ）および４７μＬ（０．２７ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜８０％アセトニトリル／水（ギ酸を０．１％含む））続いて、順相クロマトグラフィー（ＮＨ₂でキャップしたシリカ、１〜２０％ＭｅＯＨ／ＤＣＭ）で精製する。収量：３ｍｇ（３％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４３０；ｔＲ＝１．０１分。 I-45) N- {5- [4-Ethyl-6- (4-methoxypiperidin-1-yl) -pyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -methanesulfonamide

To 80 mg (0.23 mmol) E-1 in 2 mL dioxane and 1 mL DMF was added 29 mg (0.25 mmol) 4-methoxypiperdine and 47 μL (0.27 mmol) diisopropylethylamine. The reaction mixture is stirred in a microwave oven at 130 ° C. for 1 hour. Reaction mixture was reverse phase chromatographed (C18, 5-80% acetonitrile / water with 0.1% formic acid) followed by normal phase chromatography (NH ₂ capped silica, 1-20% MeOH / DCM). Purify with. Yield: 3 mg (3%). HPLC-MS: M + H = 430; tR = 1.01 min.

２ｍＬのジオキサンと１ｍＬのＤＭＦとの中の８０ｍｇ（０．２３ｍｍｏｌ）のＥ−１に、２５ｍｇ（０．２５ｍｍｏｌ）の４−ヒドロキシピペリジン（ｈｙｄｒｏｘｙｐｉｐｅｒｄｉｎｅ）および４７μＬ（０．２７ｍｍｏｌ）のジイソプロピルエチルアミンを添加し、反応混合物を、マイクロ波オーブン中、１３０℃で１時間撹拌する。反応混合物を逆相クロマトグラフィー（Ｃ１８、５〜７０％アセトニトリル／水（ＮＨ₃ＯＨを２．５％、ＮＨ₄ＨＣＯ₃を２．５％含む））続いて、順相クロマトグラフィーで精製する。収量：２ｍｇ（２％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４１４；ｔＲ＝０．８７分。 I-46) N- {5- [4-Ethyl-6- (4-hydroxypiperidin-1-yl) -pyrimidin-5-ylethynyl] -2-methylpyridin-3-yl} -methanesulfonamide

To 80 mg (0.23 mmol) E-1 in 2 mL dioxane and 1 mL DMF was added 25 mg (0.25 mmol) 4-hydroxypiperidine and 47 μL (0.27 mmol) diisopropylethylamine. The reaction mixture is stirred in a microwave oven at 130 ° C. for 1 hour. The reaction mixture was purified by reverse phase chromatography (C18,5~70% acetonitrile / water (NH ₃ OH 2.5%, including NH ₄ HCO ₃ 2.5%)) Subsequently, purified by normal phase chromatography. Yield: 2 mg (2%). HPLC-MS: M + H = 414; tR = 0.87 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、７０ｍｇ（０．６１ｍｍｏｌ）のメタンスルホニルクロリドおよび７２μＬ（０．９１ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、反応混合物を４ｍＬの酢酸エチルで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：３２ｍｇ（１８％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４０４；ｔＲ＝０．６５分。 I-81) N- [2-Methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -methylsulfonamide

70 mg to 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) methanesulfonyl chloride and 72 μL (0.91 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added and the reaction mixture is extracted 3 times with 4 mL of ethyl acetate. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 32 mg (18%). HPLC-MS: M + H = 404; tR = 0.65 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１６０ｍｇ（０．６１ｍｍｏｌ）の２，４−トリフルオロメトキシベンゼンスルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：１１５ｍｇ（６８％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５５０；ｔＲ＝０．９２分。 I-82) 2-trifluoromethoxy-N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

160 mg in 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) 2,4-trifluoromethoxybenzenesulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 115 mg (68%). HPLC-MS: M + H = 550; tR = 0.92 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１６０ｍｇ（０．６１ｍｍｏｌ）の２，４−トリフルオロメトキシベンゼンスルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：１２４ｍｇ（７６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５３４；ｔＲ＝０．８９分。 I-83) 2-Trifluoromethyl-N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

160 mg in 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) 2,4-trifluoromethoxybenzenesulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 124 mg (76%). HPLC-MS: M + H = 534; tR = 0.89 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１３０ｍｇ（０．６１ｍｍｏｌ）の４−クロロベンゼンスルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：１０５ｍｇ（７６％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５００；ｔＲ＝０．９１分。 I-84) 4-Chloro-N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -benzenesulfonamide

To 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM was added 130 mg (0.61 mmol) 4-chlorobenzenesulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 105 mg (76%). HPLC-MS: M + H = 500; tR = 0.91 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１１２ｍｇ（０．６１ｍｍｏｌ）の５−クロロ−チオフェン−２−スルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：１０１ｍｇ（６５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝５０６／５０８；ｔＲ＝０．９１分。 I-85) 5-Chloro-N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -thiophene-2-sulfonamide

112 mg of 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) 5-chloro-thiophene-2-sulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 101 mg (65%). HPLC-MS: M + H = 506/508; tR = 0.91 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１１２ｍｇ（０．６１ｍｍｏｌ）のチオフェン−２−スルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：９５ｍｇ（６５％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４７２；ｔＲ＝０．８２分。 I-86) N- [2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-yl] -thiophene-2-sulfonamide

112 mg of 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) thiophene-2-sulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 95 mg (65%). HPLC-MS: M + H = 472; tR = 0.82 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１１１ｍｇ（０．６１ｍｍｏｌ）の１−メチル−１Ｈ−ピラゾール−５−スルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：３２ｍｇ（２２％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４７０；ｔＲ＝０．７８分。 I-87) N- [2-methoxy-5- [2- (4-methyl-6-morpholin-4-ylpyrimidin-5-yl) ethynyl] pyridin-3-yl] -2-methylpyrazole-3- Sulfonamide

111 mg of 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) 1-methyl-1H-pyrazole-5-sulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 32 mg (22%). HPLC-MS: M + H = 470; tR = 0.78 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１１１ｍｇ（０．６１ｍｍｏｌ）の１−メチル−１Ｈ−ピラゾール−４−スルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：１０１ｍｇ（７０％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４７０；ｔＲ＝０．７２分。 I-88) N- [2-methoxy-5- [2- (4-methyl-6-morpholin-4-ylpyrimidin-5-yl) ethynyl] pyridin-3-yl] -1-methylpyrazole-4- Sulfonamide

111 mg of 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) 1-methyl-1H-pyrazole-4-sulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 101 mg (70%). HPLC-MS: M + H = 470; tR = 0.72 min.

５ｍＬのＤＣＭ中の１００ｍｇ（０．３１ｍｍｏｌ）の２−メトキシ−５−（４−メチル−６−モルホリン−４−イルピリミジン−５−イルエチニル）−ピリジン−３−イルアミン（Ｅ−９）に、１１１ｍｇ（０．６１ｍｍｏｌ）の５−メチルフラン−２−スルホニルクロリドおよび７２μＬ（０．９７ｍｍｏｌ）のピリジンを添加し、反応混合物を室温で終夜撹拌する。水（２ｍＬ）を添加し、混合物を５分間振盪し、水相を、分離し、４ｍＬのＤＣＭで３回抽出する。合わせた有機相を、ＭｇＳＯ₄上で乾燥し、減圧下で濃縮する。粗生成物を逆相クロマトグラフィー（Ｃ１８、２０〜８０％ＡＣＮ／水（ギ酸を１％含む））で精製する。収量：７８ｍｇ（５４％）。ＨＰＬＣ−ＭＳ：Ｍ＋Ｈ＝４７０；ｔＲ＝０．８３分。 I-89) N- [2-methoxy-5- [2- (4-methyl-6-morpholin-4-ylpyrimidin-5-yl) ethynyl] pyridin-3-yl] -5-methylfuran-2- Sulfonamide

111 mg of 100 mg (0.31 mmol) 2-methoxy-5- (4-methyl-6-morpholin-4-ylpyrimidin-5-ylethynyl) -pyridin-3-ylamine (E-9) in 5 mL DCM (0.61 mmol) 5-methylfuran-2-sulfonyl chloride and 72 μL (0.97 mmol) pyridine are added and the reaction mixture is stirred at room temperature overnight. Water (2 mL) is added, the mixture is shaken for 5 minutes, the aqueous phase is separated and extracted 3 times with 4 mL DCM. The combined organic phases are dried over MgSO ₄ and concentrated under reduced pressure. The crude product is purified by reverse phase chromatography (C18, 20-80% ACN / water with 1% formic acid). Yield: 78 mg (54%). HPLC-MS: M + H = 470; tR = 0.83 min.

Inhibition of PIP-2 Phosphorylation Induced by Biological Methods PI3Kα This PI3Kα assay provides an IC ₅₀ value indicative of the activity of a compound that inhibits PI3 kinase α activity. Inhibition of PI3 kinase is expected to show activity in treating excessive or abnormal cell growth conditions such as cancer. JA Engelman, Nature Reviews Cancer, 2009, 9, 550-562; A. Carnero, Expert Opin. Investig. Drugs, 2009, 18, 1265-1277; and P. Liu et al., Nature Reviews Drug Discovery, 2009, 8 , 627-64.

Method type: Filter binding assay Materials Assay Buffer:
40 mM HEPES pH 7.5 SIGMA H-3375
100 mM NaCl Merck 1.064.041.000
1 mM EGTA SIGMA E-4378
1 mM β-glycerophosphate SIGMA G-6253
7 mM MgCl2 Merck 58.331.000
1 mM DTT SIGMA D-0632
(0.1% BSA only during preparation of lipid mixture after sonication)
Phospholipid blend mixture (= substrate) from Avanti Polar Lipids (# 790770):
Phosphatidylinositol-4,5-bisphosphate (# 840046) 3.665%
Phosphatidylethanolamine (# 83022) 39.26%
Phosphatidylserine (# 830032) 36.66%
Sphingomyelin (# 860062) 3.665%
Phosphatidylcholine (# 830053) 16.75%
Per aliquot lipid (16.6 mg): 26 mL assay buffer + 520 μL BSA (5%)

PI3 kinase α was expressed in SF9 insect cells, co-infected with viruses encoding p85α and His-p110α, and purified by a combination of Ni-affinity chromatography and anion exchange chromatography. Aliquot into desired amount and store at -80 ° C. Final assay concentration is 25 ng / well.
Phosphotyrosine PDGFRβ-peptide H-CGG-pY-MDMSKDESVD-pY-VPMLDM-NH2 was synthesized by Jerini Peptide Technologies (JPT) and used at a final concentration of 1.7 μM (100 μM stock solution was DTT in assay buffer) And was aliquoted to the desired amount and stored at -80 ° C).
Unlabeled ATP (from Sigma; A-7699), stock solution (aqueous solution) used at a final concentration of 100 μM, 1 μM in the assay [33P] -ATP, 370 MBq / mL, 0.5 μCi / well (from Amersham (# AH9968)) Used at 10 mCi / mL) Clear 96-well plate, from Greiner (# 655162) Filter plate: Perkin Elmer UniFilter GF / B # 600005177
Microscint 0 (from Perkin Elmer, # 6013611)

2. Assay Procedure Lipid vesicles containing substrate are dissolved in 50 mL Falcon (with fresh addition of BSA) to a concentration of 0.637 mg lipid blend mixture / assay buffer (mL) and kept on ice, Subsequently, it is processed with ultrasonic waves (four 15-second pulses followed by a 10-second pause). Compounds are serially diluted in assay buffer + 6% DMSO and 10 μL of each dilution is added per well of a 96-well plate (compounds are tested in duplicate) and PDGFR-peptide (0.1% final concentration). 5 μM) and 30 μL lipid vesicles containing PI3Kα (final concentration 25 ng / well). The mixture is then incubated for 20 minutes at room temperature. Subsequently, 20 μL of assay buffer containing 3 μM unlabeled ATP and 0.5 μCi / 20 μL 33P-ATP is added. The plate is then incubated for 120 minutes at room temperature (while shaking at 300 rpm).

The reaction mixture is transferred onto the filter plate using a “filtermate harvester” from Packard, the filter plate is rinsed with PBS, then the reaction mixture is filtered on the filter plate and washed 5 times with PBS. Wash and dry at 50 ° C. for 30-60 minutes. Seal the bottom of the plate with a Perkin Elmer white sticky foil, add Microscint 0 at 25 μL / well, cover the top with a clear sticky foil, and measure the plate on a Wallac Trilux 1450 Microbeta counter.
As a positive control, a well containing a medium control (1% DMSO / assay buffer) and showing uninhibited kinase activity (high value) is useful. Wells containing assay buffer instead of enzyme can serve as a control for background activity (low values).

3. Evaluation IC ₅₀ values are calculated using the Smiley program (based on Grappad Prism).
Alamar Blue-H460, MB453, U87, MCF7 and BT474 Cell Assays The H460, MB453, U87, MCF7 and BT474 Alamar Blue cell assays are respectively H460 (human non-small cell carcinoma cell line), MB-453 ( EC ₅₀ values are provided that show the anti-proliferative or cytotoxic effects of compounds on breast cancer cell lines), U87 (glioblastoma cell lines), MCF7 (breast cancer cell lines) and BT474 (breast cancer cell lines). As is known in the art, anti-proliferative or cytotoxic effects on this cell line are expected to show activity in treating lung, breast and brain cancer. R. Marone R et al. Biochim. Biophys. Acta. 2008 Jan; 1784 (1): 159-85; S. Yaguchi et al., J. Natl. Cancer Inst. 2006 Apr 19; 98 (8): 545- See 56.

Type of method: anti-proliferation / cytotoxicity Description Alamar Blue (R) is designed to provide a rapid and sensitive measure of cell proliferation and cytotoxicity in various cell lines of humans and animals. The assay is based on the reduction of alamar blue in the reducing environment of living (metabolically active) cells. In the presence of added cytotoxic or antiproliferative compounds, native metabolic activity is halted.
Alamar Blue is soluble in the medium and is stable in the medium. Measurements are made fluorometrically by exciting at 530-560 nm and measuring emission at 590 nm. In reporting the% decrease in Alamar Blue by observing fluorescence, the data is expressed as fluorescence emission intensity units as a function of incubation time.

2. Cells and reagents H460 cells Human lung cancer cells (ATCC HTB-177)
Alamar Blue Serotec Ltd
PBS (Ca and Mg free) Life Technologies, Gibco BRL (Cat. No. 4190-094)
RPMI 1640 Medium Life Technologies, Gibco BRL (Cat. No. 61870-010)
Fetal bovine serum Life Technologies, Gibco BRL (Cat. No. 10270-106)
BT-474 cell human breast cancer cell line (ATCC HTB-20)
Alamar Blue Serotec Ltd
IMDM medium Cambrex Biowhitetaker (Cat. No. BE-12-722F)
NEAA
Sodium pyruvate (Sodiumpyruvat)
PBS (Ca and Mg free) Life Technologies, Gibco BRL (Cat. No. 4190-094)
Fetal bovine serum Life Technologies, Gibco BRL (Cat. No. 10270-106)
MCF7 cell Human breast cancer cell line Alamar Blue Serotec Ltd
IMDM medium Cambrex Biowhitetaker (Cat. No. BE-12-722F)

NEAA
Sodium pyruvate PBS (Ca and Mg free) Life Technologies, Gibco BRL (Cat. No. 4190-094)
Fetal bovine serum Life Technologies, Gibco BRL (Cat. No. 10270-106)
U-87MG cells Human glioblastoma cells (ATCC HTB-14)
CyQuant NF assay Invitrogen Cat. # C35006
PBS (Ca and Mg free) Life Technologies, Gibco BRL (Cat. No. 4190-094)
RPMI 1640 Medium Life Technologies, Gibco BRL (Cat. No. 61870-010)
Fetal bovine serum Life Technologies, Gibco BRL
(Cat. No. 10270-106)
MB453 cells MDA MB453 cells (ATCC HTB-131)
Alamar Blue Serotec BUF012B
RPMI
Fetal bovine serum Life Technologies, Gibco BRL (Cat. No. 10270-106) (phenol red, L-glutamine free)

3. Apparatus 96-well plate, flat bottom (Falcon, Cat. No .: 353072)
96 well plate, U-shaped (Costar, Cat. No .: 3799)
CO ₂ - incubator microplate reader, Spectramax Plus, Molecular Devices

4). Typical procedure day 0:
In a flat bottom 96-well plate, seed 3000 BT-474 cells (IMDM / 5% FCS, 1% NEAA, 1% sodium pyruvate) in 150 μL medium (including medium blank).
Plates are incubated overnight at 37 ° C. in a CO ₂ incubator.
Day 1:
Compounds are diluted to a concentration of 40 μM in 96 well plates, then 10 dilution steps 1: 3 in medium.
Add 50 μL of each dilution per well (200 μL total volume per well, final concentration of compound: 10 μM, then 1: 3). If necessary, further dilutions are tested.
All concentrations are tested in duplicate.
Control: cells without compound (+50 μL medium / DMSO).
Cells are incubated with compound for 5-6 days.
Day 6 or 7:
Add 25 μL of Alamar Blue solution to each well and incubate at 37 ° C. for 8 hours.
Fluorescence is measured by exciting at 530-560 nm and measuring emission at 590 nm.

5. Evaluation The average value of the blank medium is subtracted from the specimen reading and the EC ₅₀ is calculated using GraphPad Prism (Fifty).

  Based on these biological properties, the compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and all the above mentioned forms of salts Suitable for treating diseases characterized by excessive or abnormal cell proliferation or by abnormal activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway.

  Such diseases include, for example, viral infections (eg, HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacteria, fungi and Parasitic infections; leukemias, lymphomas and solid tumors (eg cancer and sarcomas), skin diseases (eg psoriasis); cells (eg fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells) Or diseases based on hyperplasia characterized by an increase in the number of epithelial cells (eg endometrial hyperplasia); bone diseases and cardiovascular diseases (eg restenosis and hypertrophy).

  For example, the compounds according to the invention can treat, but are not limited to, the following cancers: eg brain tumors such as acoustic schwannomas; ciliary astrocytomas, fibrous astrocytomas, protoplasts Astrocytoma, astrocytoma such as large round cell astrocytoma, atypical astrocytoma and glioblastoma; brain lymphoma; brain metastasis; pituitary tumor such as prolactinoma; HGH (human growth hormone) Producing tumors and ACTH (adrenocorticotropic hormone) producing tumors; craniopharyngioma, medulloblastoma, meningioma and oligodendroglioma; neural tumors (neoplasms) such as tumors of the vegetative nervous system, eg sympathetic neuroblasts Cytomas, ganglion neuromas, paragangliomas (pheochromocytoma, pheochromocytoma) and carotid body tumors; stump neuromas, neurofibromas, schwannomas (neurofibromas, Schwann) Cell tumor) and malignant schwannoma Tumors on any peripheral nervous system; and central nervous system tumors such as brain and bone marrow tumors; intestinal cancers such as rectal cancer, colon cancer, colorectal cancer, anal cancer, colon cancer, small intestine and duodenal tumors; Eyelid tumors such as basal cell carcinoma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder; eg small cell bronchial carcinoma (oat cell carcinoma) and non-small cell bronchial carcinoma (NSCLC) (squamous epithelium Breast cancer such as breast cancer such as invasive ductal cancer, colloidal cancer, lobular invasive cancer, tubular cancer, adenocarcinomas and papillary cancer, etc. Non-Hodgkin lymphoma (NHL) such as Burkitt lymphoma, low malignant non-Hodgkin lymphoma (NHL) and mushroom-like mucositis; uterine cancer or endometrial cancer or uterine body cancer; CUP symptoms (Unknown primary cancer); ovarian cancer or ovarian cancer such as mucinous, endometrial or serosal cancer; gallbladder cancer; bile duct cancer such as crackin tumor; eg seminoma and non Testicular cancer such as seminoma; for example, malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL) (chronic lymphocytic leukemia, leukemic reticuloendotheliosis, immunocytoma, platelet cell tumor (multiple myeloma) Lymphomas (lymphosarcoma) such as, immunoblastoma, Burkitt lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastoma and lymphoblastoma); for example, vocal cord tumors, upper glottis, glottis And laryngeal cancers such as subglottic laryngeal tumors; eg osteochondroma, chondroma, chondroblastoma, chondromyxoma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant Cell tumor, chondrosarcoma, osteosarcoma, Yui Bone cancers such as gingival sarcoma, reticulosarcoma, plasmacytoma, fibrous dysplasia, juvenile bone cyst and aneurysm bone cyst; eg lips, tongue, mouth floor, oral cavity, gingiva, palate, salivary gland, throat, Head and neck tumors such as nasal cavity, paranasal sinus, laryngeal and middle ear tumors; liver cancer such as hepatocellular carcinoma or hepatocellular carcinoma (HCC); leukemia such as acute lymphoblastic / lymphoblastic leukemia (ALL) Acute leukemia such as acute myeloid leukemia (AML); chronic leukemia such as chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML); eg papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, glandular epithelium Abdominal cancer or gastric cancer such as cancer, small cell carcinoma and undifferentiated cancer; melanoma such as superficial, nodular, malignant or terminal mole melanoma; eg renal cell carcinoma or adrenal gland Or a Grawitz tumor Visceral cancer; Esophageal cancer or cancer of the esophagus; Penile cancer; Prostate cancer; Pharyngeal cancer or pharyngeal cancer such as nasopharyngeal cancer, oropharyngeal cancer and hypopharyngeal cancer; Retinoblastoma; squamous cell carcinoma, adenocarcinoma, in situ cancer, malignant melanoma and sarcoma; thyroid cancer such as papillary, follicular and medullary thyroid and undifferentiated cancer; spine cell carcinoma, epidermoid carcinoma And squamous cell carcinoma of the skin; thymoma; cancer of the urethra, and cancer of the vulva.

  Preferred cancer types that may be treated with the compounds of the invention are those whose pathways are activated by PI3K mutations or PTEN deletions. Preferred cancers that can be treated with the compounds according to the invention are cancers of the lung, liver, colon, brain, breast, ovary and prostate.

The novel compounds may optionally be used for the prevention, short-term or long-term treatment of the aforementioned diseases, optionally further radiation therapy, or other “latest level” compounds such as cytostatic or cytotoxic substances, cell growth inhibition It can be used in combination with drugs, angiogenesis inhibitors, steroids or antibodies.
The compounds of general formula (1) can be used alone or in combination with other active substances according to the invention and optionally in combination with other pharmacologically active substances.

  Chemotherapeutic agents that can be administered in combination with the compounds according to the present invention include, but are not limited to, hormonal agents, hormone analogs and anti-hormonal agents (eg, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate , Flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide); aromatase inhibitors (eg, anastrozole, letrozole, riarosol) , Borozole, exemestane, atamestan); LHRH agonists and antagonists (eg goserelin acetate, luprolide); growth factors (eg “platelet-derived growth factor” and “hepatocyte growth factor” Inhibitors of growth factors such as "growth factor" antibodies, "growth factor receptor" antibodies and tyrosine kinase inhibitors such as cetuximab, gefitinib, imatinib, lapatinib and trastuzumab Antimetabolites (eg antifolates such as methotrexate, raltitrexed, pyrimidine analogues (such as 5-fluorouracil), capecitabine and gemcitabine, purines and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, Cytarabine, fludarabine); antitumor antibiotics (eg, anthracyclines such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, pre Platinum derivatives (eg, cisplatin, oxaliplatin, carboplatin); alkylating agents (eg, estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitroso) Urea (eg, carmustine and lomustine, thiotepa)); antimitotic agents (eg, vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (eg, epipomase) Dofilotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone); And various chemotherapeutic agents such as amifostine, anagrelide, clodronate, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotan, pamidronate, and porfimer.

  Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxycytidine, 2-methoxyestradiol, 2C4, 3-alletin, 131-I-TM-601, 3CPA, 7-ethyl-10- Hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, Aldesleukin, Alitretinoin, Altretamine, Arbocidib, Amonafide, Anthrapyrazole, AG-2037, AP-5280, Apadicon, Apomine, Alanose, Algravin, Arzoxifene, Atamestan , Atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, ARRY-300, ARRY-142886 / AZD-6244, ARRY-704 / AZD-833 AS-703026, azacitidine, aza epothilone B, azonafide, BAY-43-9006, BBR-3464, BBR-3576, bevacizumab, bilicodal dicitrate, BCX-1777, bleosine, BLP-25, BMS-184476, BMS- 247550, BMS-188797, BMS-275291, BNP-1350, BNP-7787, BIBW2992, BIBF1120, bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1, bortezomib, brostalicin, busulfan, CA-4 prodrug, CA- 4, CapCell, calcitriol, caneltinib, camphosphamide, capecitabine, carboxyphthalatoplatin, CCI-779, CEP-701, CEP 751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, sermoleukin, semadotin, CH4987655 / RO-4987655, chlorotrianicene, sirengitide, cyclosporine, CDA-II, CDC-394, CKD-602, clofarabine, cortisine, Combretastatin A4, CHS-828, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D24851, decitabine, deoxorubicin, deoxyrubicin, deoxyco Formycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestro , Difluotecan, zidox, DMDC, dolastatin 10, dranidazole, E7010, E-6201, edatrexat, edreotide, efaproxiral, eflornithine, EKB-569, EKB-509, elsamitrucin, epothilone B, epratuzumab ER-65 , Erlotinib, ET-18-OCH3, ethynylcytidine, ethinylestradiol, exatecan, exatecan mesylate, exemestane, excislind, fenretinide, floxuridine, folic acid, FOLFOX, FOLFIRI, formestane, galarrubicin, f gal init ), Gemtuzumab, gimatecan, glufosfamide, GCS-IOO, G17D Immunogen, GMK, GPX-100, GSK-5126766, GSK-1120212, GW2016, granisetron, hexamethylmelamine, histamine, homohalintonin, hyaluronic acid, hydroxyurea, caproic acid hydroxyprogesterone, ibandronomab, ibritumomab, idetrexate IDN-5109, IMC-1C11, Immunol, Indislam, Interferon α-2a, Interferon α-2b, Interleukin-2, Ionafarnib, Iproplatin, Irofulvene, Isohomohalichondrin-B, Isoflavone, Isotretinoin, Ixabepilone JRX-2, JSF-154, J-107088, complex estrogen, Kahalide F, ke Conazole, KW-2170, Lovaplatin, Leflunomide, Lenograstim, Leuprolide, Leuporerin, Lexidronam, LGD-1550, Linezolid, Lutetium Texaphyrin, Lometrexol, Losoxantrone, LU223651, Lurtotecan, Mafosftamone, Methylestadone -10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid, mitomycin, mibobrin, MK-2206, MLN518, motexafingadolinium, MS-209, MS-275, MX6, neridronate, neobasstat, nimesulide, nitro Glycerin, noratrexed, norelin, N-acetylcysteine, 6-Benzylguanine, Omeprazole, Oncophage, Olmiplatin, Altataxel, Oxanthrazole, Estrogen, Patupilone, Pegfilgrastim, PCK-3145, Pegfilgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P- 04, PKC412, P54, PI-88, peritinib, pemetrexed, pentrix, perifosine, perillyl alcohol, PG-TXL, PG2, PLX-4032 / RO-5185426, PT-100, picoplatin, pivaloyloxymethyl butyrate, pixantrone , Phenoxodiol O, PKI166, previtrexed, pricamycin, polyprenic acid, porphyromycin, prednisone, prednisolone, quinamedo, quinupristin, R AF-265, Ramosetron, Lampyrinase, RDEA-119 / BAY869766, Rebeccamycin analog, Lebimide, RG-7167, Rhizoxin, rhu-MAb, Risedronate, Rituximab, Rofecoxib, Ro-31-7453, RO-5126766, RPR109881A, Rubidazone , Rubitecan, R-flurbiprofen, S-9788, sabarubicin, SAHA, salgramostim, satraplatin, SB408075, SU5416, SU6668, SDX-101, semustine, theocalcitol, SM-11355, SN-38, SN-4071 SR-27897, SR-31747, SRL-172, Sorafenib, Spiroplatin, Squalamine, Suberanohydroxamic acid, Sutent, T 00607, T138067, TAS-103, Tazedinarine, Talaporfin, Talyquital, Taxotere, Taxoplexin, Tazarotene, Tegafur, Temozolamide, Tesmilifene, Testosterone, Testosterone propionate, Tesmilifene, Tetraplatin, Tetrodotoxin, L , Timectacin, thiazofurin, tipifarnib, tirapazamine, tocladecine, tomdex, tremofine, trabectadine, trans MID-107, transretinoic acid, trastuzumab, tretinoin, triacetyluridine, triapine, trimethrexate, TLK58286D Valrubicin Batalanib, vincristine, vinflunine, virulidine, WX-UK1, Vectibix, Xeloda, XELOX, XL-281, XL-518 / R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, zoledronate and zoskidal.

Suitable formulations include, for example, tablets, capsules, suppositories, solutions, in particular injections (subcutaneous, intravenous, intramuscular) and infusion solutions-elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound is generally 0.1 to 90% by weight of the composition, preferably 0.5 to 50% by weight, ie to achieve the dosage range specified below. The amount should be sufficient. The specified dose can be given several times a day if necessary.
Suitable tablets are, for example, active substances known excipients, eg inert diluents such as calcium carbonate, calcium phosphate or lactose; disintegrants such as corn starch or alginic acid; binders such as starch or gelatin; magnesium stearate Or by mixing with a lubricant such as talc; and / or a release-retarding agent such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. A tablet can also include several layers.
Coated tablets are prepared by coating a core made in the same way as a tablet with materials commonly used to coat tablets, such as Kollidon or shellac, gum arabic, talc, titanium dioxide, or sugar. can do. The core can also consist of several layers in order to achieve delayed release or to prevent contraindications. Similarly, the tablet coating can consist of several layers, possibly using the excipients mentioned earlier in relation to the tablets to achieve delayed release.

A syrup or elixir comprising an active substance according to the invention or a combination thereof further comprises a sweetener such as saccharin, cyclomate, glycerol or sugar and a flavor enhancer, for example a flavor such as vanillin or orange extract. Can do. They can also contain suspending aids or thickeners such as sodium carboxymethylcellulose; wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide; or preservatives such as p-hydroxybenzoates.
Solutions for injection and infusion are optionally added in a conventional manner, for example, by adding a tonicity agent, a preservative such as p-hydroxybenzoate, or a stabilizer such as an alkali metal salt of ethylenediaminetetraacetic acid. Even when prepared using emulsifiers and / or dispersants and using water as a diluent, for example, organic solvents may be used as solvate formers or solubilizers, such as injection vials or Transfer into ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances are prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and packing them into gelatin capsules. be able to.
Suitable suppositories can be prepared, for example, by mixing with a carrier such as neutral fat or polyethylene glycol or its derivatives, prepared for this purpose.
Excipients that can be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffin (eg petroleum fractions), vegetable oils (eg peanut or sesame oil), monohydric or polyhydric alcohols (eg Ethanol or glycerol), carriers such as natural mineral powders (eg kaolin, clay, talc, chalk), synthetic mineral powders (eg highly dispersible silicic acid and silicates), sugars (eg sucrose, lactose and glucose) Emulsifiers such as lignin, sulfite waste liquors, methylcellulose, starch and polyvinylpyrrolidone, and lubricants such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
The formulations are administered in the usual manner, preferably by oral or transdermal route, most preferably by oral route. For oral administration, the tablets will, of course, contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate in addition to the carriers described above, together with various additives such as starch, preferably potato starch, gelatin. Can be included. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used simultaneously for the tableting process. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or colorants in addition to the excipients described above.

When used parenterally, solutions of the active substance with suitable liquid carriers can be used.
When used intravenously, the dosage is 1-1000 mg / hour, preferably 5-500 mg / hour.

  When used in tablets, the dosage is 1 to 10000 mg / day per patient, preferably 10 to 1000 mg / day per patient.

  Sometimes, however, it may be necessary to deviate from the specified amount, depending on body weight, route of administration, individual response to the drug, the nature of the formulation, and the time or interval at which the drug is administered. Thus, in some cases, it may be sufficient to use less than the above minimum dose, while in other cases the upper limit should be exceeded. When administering large amounts, it may be desirable to divide those amounts into several smaller doses over the day.

Claims (18)

Formula (I):

(I)
Or a salt thereof [wherein
R ¹ is —H or —NH ₂ ;
R ² is —N (R ⁷ , R ⁸ );
R ³ is —C _1-5 alkyl;
R ⁴ is —H, halogen, —CN, —C _1-5 alkyl, —O—C _1-5 alkyl, —C _1-5 alkyl-O—C _1-5 alkyl or —O—C _1-5. Selected from haloalkyl;
R ⁵ is —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently 1 One or more ═O, —CN, ═S, halogen, R ¹⁵ or R ¹⁶ optionally substituted); or R ⁵ is —C _6-10 aryl or 5 to 12 membered Heteroaryl (all of these groups are independently selected from one or more —CN, halogen, R ¹⁵ or R ¹⁶ ); or R ⁵ is —N ( R ¹² , R ¹³ );
R ⁶ is halogen, —CN, —C _1-5 alkyl, —C _1-5 haloalkyl, —O—C _1-5 alkyl, —C _1-5 alkyl-O—C _1-5 alkyl or —O—. Selected from C _1-5 haloalkyl;
n is 0, 1 or 2;
R ⁷ is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O —R ⁹ , —C _1-5 alkyl-S—R ⁹ , or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (all of these groups independently represent one or more ═O , -CN, = S, halogen, or optionally substituted with R ¹¹ );
R ⁸ is —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl. , 3-14 membered heterocyclyl, —C _1-5 alkyl-O—R ⁹ , —C _1-5 alkyl-S—R ⁹ , or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (these All of the groups are independently selected from one or more ═O, —CN, ═S, halogen, or optionally substituted with R ¹¹ ); or R ⁷ , R ⁸ are the same Or, alternatively, from —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups may independently be substituted with one or more —CN, halogen, or R ¹¹ ). or are independently selected; or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, partially saturated or fully 3-14 membered heterocyclyl sum (base are independently one or more of = O, -CN, = S, halogen, or may be independently substituted with R ¹¹⁾ to form a;
R ⁹ is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O —C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups) Are independently selected from one or more ═O, —CN, ═S, halogen, or R ¹¹ );
R ¹⁰ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl. , —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _{1- 5} alkyl) (all of these groups are independently selected from one or more of ═O, —CN, ═S, halogen, or R ¹¹ ); or R ⁹ , R ¹⁰ are the same or different and are —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently substituted with one or more —CN, halogen, or R ^11. Or R ⁹ and R ¹⁰ together with the atoms to which they are attached, are independently selected from Forming 3 to 14 membered heterocyclyl optionally substituted by one or more ═O, —CN, ═S, halogen, or R ¹¹ ;
R ¹¹ is selected from —OH, —NH ₂ , —CF ₃ , —OCF ₃ , —OCHF ₂ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , or nitro; or R ¹¹ is —C _6-10 aryl or 5-12 membered heteroaryl (all of these groups are independently one or more of —CN, halogen, —OH, —NH ₂ , —CH ₃ , —CH _{2 CH 3, -CF 3, -S} (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl , - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3) _{, -O-CH 3, -O-} CH 2 CH 3, -S-CH 3, -C (O) NH _{H 3, -C (O) N} (CH 3) 2, -C (O) NH-CH 2 CH 3, -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, - OCF ₃ , —OCHF ₂ , —tetrahydrofuryl, —tetrahydropyranyl, —N-methylpiperazinyl, —pyrrolidinyl, —morpholinyl, or —nitro optionally substituted); or R ¹¹ Are —NH—C _1-5 alkyl, —N (C _1-5 alkyl, —C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _{1— 5} alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently one or more ═O, — CN, ═S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S ( _{O) 2 CH 3, -C (} O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - cyclohexyl, -NH-CH ₃ , —N (CH ₃ ) ₂ , —N (CH ₂ CH ₃ ) ₂ , —NH—CH ₂ CH ₃ , —N (CH ₃ , CH ₂ CH ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH ₃ ) ₂ , —C (O) NH—CH ₂ CH ₃ , —C (O) N (CH _{2 CH 3) 2, -C (} O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl or - nitro May be selected);
R ¹² is —H, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O —C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _1-5 alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups) Are independently selected from one or more ═O, —CN, ═S, halogen, or R ¹⁴ );
R ¹³ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl. , —C _6-10 aryl, 5-12 membered heteroaryl, —C _1-5 alkyl-O—C _1-5 alkyl, —C _1-5 alkyl-S—C _1-5 alkyl, or —C _{1— 5} alkyl-N (C _1-5 alkyl, C _1-5 alkyl) (all of these groups are independently substituted with one or more ═O, —CN, ═S, halogen, or R ^14. Or R ¹² , R ¹³ are the same or different and are —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently one, or -CN, halogen, or are independently selected from may also be) optionally substituted with R ^14; or R ¹² and R ¹³ , Together with the nitrogen atom to which they are attached, 3-14 membered heterocyclyl (base are independently one or more of = O, -CN, = S, substituted halogen, or R ¹⁴ May be formed);
R ¹⁴ is selected from —OH, —NH ₂ , —CF ₃ , —OCF ₃ , —OCHF ₂ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , or —nitro; or R ¹⁴ is —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups are independently one or more —CN, halogen, —OH, —NH ₂ , —CH ₃ , — _{CH 2 CH 3, -CF 3,} -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - Cyclobutyl, -cyclopentyl, -cyclohexyl, -NH-CH ₃ , -N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -NH-CH ₂ CH ₃ , -N (CH ₃ , CH ₂ CH _{3 ), - O-CH 3,} -O-CH 2 CH 3, -S-CH 3, -C (O) NHC _{3, -C (O) N (} CH 3) 2, -C (O) NH-CH 2 CH 3, -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - morpholinyl, or - is selected from may also be) optionally substituted with nitro; or R ¹⁴ is , —NH—C _1-5 alkyl, —N (C _1-5 alkyl, —C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 Alkyl, —C _2-5 alkenyl, —C _2-5 alkynyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently one or more ═O, —CN , = S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O _{) 2 CH 3, -C (O} ) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - cyclohexyl, -NH-CH _{3 , -N (CH 3) 2,} -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH 2 _{CH 3, -S-CH 3,} -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O) NHCH 2 CH 3, -C (O) N (CH 2 _{CH 3) 2, -C (O} ) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl, - a nitro - morpholinyl or, May be selected);
R ¹⁵ and R ¹⁶ are the same or different and are —OH, —NH ₂ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH ₃ , —OCF ₃ , —OCHF ₂ , or — Independently selected from nitro; or R ¹⁵ and R ¹⁶ are the same or different and are —C _6-10 aryl or 5-12 membered heteroaryl (all of these groups are independently one or more of -CN, _{halogen, -OH, -NH 2, -CH 3} , -CH 2 CH 3, -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl, - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, —NH—CH ₂ CH ₃ , —N (CH ₃ , CH ₂ CH ₃ ), —O—CH ₃ , —O—CH ₂ CH ₃ , —S—CH ₃ , —C (O) NHCH ₃ , —C (O) N (CH ₃ ) ₂ , —C (O) NH— _{CH 2 CH 3, -C (O} ) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-Mechirupiperajini R, and -pyrrolidinyl, -morpholinyl, or optionally substituted with -nitro); or R ¹⁵ and R ¹⁶ are the same or different and represent -NH-C _1-5 alkyl,- N (C _1-5 alkyl, C _1-5 alkyl), —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _2-5 alkenyl, —C _{2 -5} alkynyl, -C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently one Or a plurality of ═O, —CN, ═S, halogen, —OH, —NH ₂ , —CH ₃ , —CH ₂ CH ₃ , —CF ₃ , —S (O) ₂ CH ₃ , —C (O) CH _3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert-butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N _{(CH 2 CH 3) 2,} -NH-CH 2 CH 3, -N (CH 3, CH 2 CH 3), - O-CH 3, -O-CH 2 CH 3, -S-CH 3, -C _{(O) NHCH 3, -C (} O) N (CH 3) 2, -C (O) NHCH 2 CH 3, -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-Mechirupipera Cycloalkenyl, - pyrrolidinyl, - morpholinyl, or - or substituted with nitro independently selected from may also be); or R ¹⁵ and R ^16, together with the atoms to which they are attached, partially saturated Or fully saturated —C _3-10 cycloalkyl or 4-8 membered heterocyclyl (all of these groups are independently one or more of ═O, —CN, ═S, halogen, —OH, —NH _{2 , -CH 3, -CH 2 CH 3} , -CF 3, -S (O) 2 CH 3, -C (O) CH 3, - propyl, - isopropyl - cyclopropyl, - butyl, iso- butyl -, tert- butyl -, - cyclobutyl, - cyclopentyl, - _{cyclohexyl, -NH-CH 3, -N (} CH 3) 2, -N (CH 2 CH 3) 2, -NH-CH 2 CH 3, -N (CH _3, CH ₂ CH _{3), O-CH 3, -O-CH} 2 CH 3, -S-CH 3, -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O) NHCH 2 CH 3 , -C (O) N (CH 2 CH 3) 2, -C (O) - pyrazolidinyl, -OCF _3, -OCHF _2, - tetrahydrofuryl, - tetrahydropyranyl,-N-methylpiperazinyl, - pyrrolidinyl , -Morpholinyl, or -nitro, which may be substituted)].   The compound of claim 1, wherein n is 0. R ⁵ is —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl (all of these groups are independently one or more of ═O, —CN, ═S, halogen, , R ¹⁵ or R ¹⁶ , where R ¹⁵ and R ¹⁶ are selected as defined in claim 1 or R ⁵ is —C ₆ all _-10 aryl or 5-12 membered heteroaryl (these groups, independently, one or more of -CN, halogen, may be substituted by R ¹⁵ or R ^16, wherein, R ¹⁵ and R ¹⁶ is selected from to) defined as claimed in claim 1 a compound according to claim 1 or 2. R ⁵ is one or more in an optionally substituted 5-12 membered heteroaryl substituent as defined in claim 1. A compound according to any one of claims 1 3 . R ⁵ is pyridyl, imidazolyl, pyrazolyl, thiophenyl, furyl, N-methyl-pyrazolyl, N-methyl-imidazolyl (all of each group independently being one of the substituents as defined in claim 1 or 5. The compound of claim 4, wherein the compound is selected from a plurality of optionally substituted. R ⁵ is —C _1-5 alkyl, pyrrolidinyl, cyclopropyl, cyclohexyl or phenyl, all of which are independently substituted with one or more of the substituents as defined in claim 1 The compound according to any one of claims 1 to 3, wherein the compound is selected from: R ⁷ is —H, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl or —C _1-5 alkyl-N (R ⁹ , R ¹⁰ ) (all of these groups are Independently selected from one or more ═O, —CN, ═S, halogen or R ¹¹ ),
R ⁸ is —O—C _1-5 alkyl, —S—C _1-5 alkyl, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl or —C _1-5 alkyl— N (R ⁹ , R ¹⁰ ) (all of these groups are independently selected from one or more ═O, —CN, ═S, halogen or R ¹¹ ) Or R ⁸ is —C _6-10 aryl, 5-12 membered heteroaryl (all of these groups may independently be substituted with one or more —CN, halogen or R ¹¹ ) Selected from
R ^9, R ¹⁰ and R ¹¹ are as defined in claim 1 A compound according to any one of claims 1 to 6. R ⁷ and R ⁸ are as defined in claim 1 or 6 and together with the nitrogen atom to which they are attached, are partially saturated or fully saturated 3-14 membered heterocyclyl (the group is Independently formed by one or more ═O, —CN, ═S, halogen or R ¹¹ , where R ¹¹ is defined as in claim 1) 8. The compound according to any one of claims 1 to 7, wherein R ² may be independently substituted with one or more ═O, —CN, ═S, halogen or R ^11, where R ¹¹ is as defined in the claims. 9. A compound according to any one of claims 1 to 8 which is morpholinyl or piperazinyl. R ⁷ is selected from -C _1-3 alkyl or tetrahydropyranyl A compound according to any one of claims 1 to 7. The compound according to any one of claims 1 to 10, wherein R ⁴ is -H, -C _1-5 alkyl or -O-C _1-5 alkyl. R ⁹ is —H, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—C _1-5 alkyl, or —C _1-5 alkyl. —N (—C _1-3 alkyl, —C _1-3 alkyl) (all of these groups are independently substituted with one or more ═O, —CN, ═S, halogen or R ^11. Selected from)
R ¹⁰ is —H, —O—C _1-5 alkyl, —C _1-5 alkyl, —C _3-10 cycloalkyl, 3-14 membered heterocyclyl, —C _1-5 alkyl-O—C _1-5. Alkyl, or —C _1-5 alkyl-N (—C _1-3 alkyl, —C _1-3 alkyl) (all of these groups are independently one or more of ═O, —CN, ═S , optionally substituted with halogen or R ¹¹ is selected from may also), wherein, R ¹¹ is defined as described in claim 1 a compound according to any one of claims 1 to 11. R ¹² and R ¹³ , together with the atoms to which they are attached, are one or more ═O, —CN, ═S, halogen or R ^14, where R ¹⁴ is defined in claim 1 13. A compound according to any one of claims 1 to 12 forming a 3-14 membered heterocyclyl which is independently substituted) (defined as described).

14. A compound according to any one of claims 1 to 13, selected from:   15. A compound according to any one of claims 1 to 14 for use in the treatment of cancer.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 15.   Use of a compound according to any one of claims 1 to 14 in the treatment of cancer.   Use of a pharmaceutical composition comprising a compound according to any one of claims 1 to 14 in the treatment of cancer.